Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCOCC.[Cl:23][CH:24]([F:28])[C:25](Cl)=[O:26]>O>[Cl:23][CH:24]([F:28])[C:25]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:26]
Reactant: O=C(Cl)C(F)Cl
Reactant: Nc1ccc(Cl)cc1C(=NO)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1C(=NO)c1ccccc1)C(F)Cl
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Water, 250 ml, was added to a solution of 50 g (0.203 mole) of 2-amino-5-chlorobenzophenone oxime (mixture of isomers) in 1 l. of ether, and the mixture was stirred rapidly and cooled to 5°. Solutions of (A) 100 ml of 10% sodium hydroxide in water and (B) 33.5 g (0.228 mole) of chlorofluoroacetyl chloride made up to 100 ml with ether were simultaneously added at the same rate over 30 min., keeping the temperature of the reaction mixture at about 10° with cooling. The reaction mixture was stirred for 30 min. after the addition, and the ether layer was separated, washed with water, dried (MgSO4), and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene to give 61.2 g (88%) of 2-(chlorofluoroacetamido)-5-chlorobenzophenone oxime (mixture of isomers) as light yellow crystals, mp 110°-129°. The 19F nmr (acetone-d6) indicates a mixture of two isomers in a 70:30 ratio: δ -143.2 ppm (d, d, J=50, 2.5 Hz, 30%) and δ -144.3 ppm (d, d, J=50, 2.5 Hz, 70%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH3:26])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([O:25][CH3:26])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OC)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CO[C@@H]1C[C@H]2[C@H](C(=O)O)[C@H]2[C@]1(N)C(=O)O
Temperature: 23 °C
Yield: 83 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-azido-3-methoxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-1) (214 mg, 0.56 mmol) in HOAc (8 mL) and H2O (2 mL) was hydrogenated in the presence of Pd/C (35 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous acetic acid. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (15 mL) for 4 h. The solution was cooled to 23° C., filtered, washed with water and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (10 mL) and propylene oxide (5.6 mL) and refluxed for 15 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-methoxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (I-7) (100 mg 74%) as a white solid. 1H-NMR (250 MHz, D2O) □1.86 (1H, t, J=3.5 Hz), 2.04-2.23 (3H, m), 2.50 (1H, dd, J=12, 7 Hz), 3.29 (3H, s), 3.62 (1H, bt,J=8 Hz); MS[ISN] 214 [(M-H)- ]; mp>250° C.; □D20 -13.84° (c=1.01, H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.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>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][CH:14]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccc(Br)nc1
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: CCOC(C)=O
Solvent: CCO
Product: Fc1ccccc1-c1ccc(Br)cn1
Temperature: 80 °C

Procedure:
Under nitrogen, 39.2 g (0.28 mol) of 2-fluoro-phenylboronic acid, 59.9 g (0.25 mol) of 2,5-dibromopyridine and 2.17 g of tetrakis(triphenylphosphine)palladium were dissolved in 420 ml of ethanol and 840 ml of toluene. 840 ml of a 2 N sodium carbonate solution were added, and the mixture heated to 80° C. for 1 h. Afterwards the mixture was cooled to 5 to 10° C., 800 ml of ethyl acetate were added, and the precipitated salts were separated by filtration. The organic phase of the mother liquor was separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([O:21][CH2:22][O:23][CH3:24])[CH:3]=1.[C-:25]#[N:26].[K+].CS(C)=O.C(OCC)(=O)C>O>[C:25]([C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([O:21][CH2:22][O:23][CH3:24])[CH:3]=1)#[N:26]
Reactant: COCOc1cc(F)c(F)cc1C(=O)c1ncccc1OCOC
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cc(C#N)c(F)cc1C(=O)c1ncccc1OCOC
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 2-(4,5-difluoro-2-methoxymethoxybenzoyl)-3-methoxymethoxy pyridine (7.18 g), potassium cyanide (4.47 g) and DMSO (100 ml) was stirred at 34°-40° C. overnight. To the reaction mixture were added ethyl acetate and water for extraction. The organic layer was washed with water and a saturated aqueous saline solution, successively, which was then dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give a mixture (7.05 g) of 2-(4-cyano-5-fluoro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine and the starting compound (5:1). To this mixture (6.98 g) were added methanol (100 ml) and conc. hydrochloric acid (5 ml), which was stirred at 60° C. overnight. The reaction mixture was cooled by aeration, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic solvent was dried (anhydrous magnesium sulfate). The solvent was distilled under reduced pressure. The residue was washed with isopropylether to give 2-(4-cyano-5-fluoro-2-hydroxybenzoyl)-3-hydroxypyridine as crude crystals (4.59 g). This crude crystalline product was, without further purification subjected to reaction, in accordance with the method in Example 1, to lead to its oxime to give (Z)-2-(4-cyano-5-fluoro-2-hydroxybenzoyl)-3-hydroxyoyridine O-t-butyloxime (2.46 g) (Compound 176).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1.C([N:36]1[CH:40]=[C:39]([C:41](=[O:44])[CH2:42][CH3:43])[N:38]=[CH:37]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:44][C:41]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1)([C:39]1[N:38]=[CH:37][NH:36][CH:40]=1)[CH2:42][CH3:43]
Reactant: CN1Cc2c(ccc3cc(Br)ccc23)C1=O
Reactant: CCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCC(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1c[nH]cn1
Yield: 67.1 %

Procedure:
By the reaction in the same manner as in Example 18 using 7-bromo-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.14 g) and 1-(1-trityl-1H-imidazol-4-yl)-1-propanone (0.17 g), the title compound (0.10 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:5][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([F:31])[CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[CH2:3][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([F:31])[CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)OC(C)(C)C)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.8 %

Procedure:
To a vial containing tert-butyl 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoate (12.0 mg, 0.0280 mmol) was added methylene chloride (0.140 mL) and trifluoroacetic acid (0.140 mL, 0.0280 mmol). The reaction was stirred at room temperature for 1.5 h. The mixture was concentrated and azeotrophed with toluene to provide crude 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoic acid (11 mg, 99% yield) as an oil. (M+1): 379.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3c(c2=O)Cc2ccc(Cl)cc2N3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c2c(c(O)nn1-c1ccc(O)cc1)Nc1cc(Cl)ccc1C2
Temperature: 0 °C
Yield: 48 %

Procedure:
To a mixture of the 7-chloro-4-hydroxy-2-(4′-methoxyphenyl)-5,10-dihydro-2H-pyridazino[4,5-b]quinoline-1-one (521 mg) in methylene chloride (50 mL), cooled in an ice/water bath, was added BBr3 dropwise (0.300 mL). The mixture was stirred with cooling for 15 minutes. The cooling bath was removed and the reaction was stirred at room temperature for 3 hours. The resulting solution was cooled to 0° C. and saturated NaHCO3 (55 mL) was added. The resulting mixture was stirred for 20 minutes, then the pH was adjusted with 6N HCl to pH=2. This was stirred for 15 minutes and the mixture was neutralized with saturated NaHCO3. The mixture was filtered and the paste residue was washed twice with ethyl acetate. The crude solid was taken in water (25 mL) and extracted three times with ethyl acetate/THF (4:1). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to dryness. The residue was triturated in ethyl acetate to afford the title compound as a yellow solid (48%). mp 210-212° C. (decomp.); MS 342(m+H); NMR 3.78(s,2H), 7.69(d,2H,J=8.8 Hz), 6.92(dd,1H,J1=8 Hz,J2=2 Hz), 7.10(d,1H,J=8 Hz), 7.20(d,1H,J=2 Hz), 7.26(d,2H,J=8.8 Hz), 9.0 (s,1H), 9.59(bs,1H), 1.95(bs,1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1>C(O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1
Reactant: COC(=O)/C=C/c1cccc(CO)c1
Solvent: CCO
Product: COC(=O)CCc1cccc(CO)c1
Reaction time: 20 h
Yield: 83.2 %

Procedure:
(Ph3P)3RhCl (11.5 mg, 0.012 mmol) was added to a solution of 17 (25 mg, 0.13 mmol) in 0.400 mL ethanol. The reaction was stirred under 1 atm H2 balloon for 20 h and then was filtered through Celite. Evaporation to dryness and purification by flash chromatography on silica gel (30% ethyl acetate/hexanes) gave compound 18 (21 mg, 82%).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:31]([CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:32][CH:33]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(-c5cccc(CN(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (45.0 mg, 0.236 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.039 g, 36%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.5 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J=7.1 Hz, 1H), 7.55-7.50 (m, 3H), 7.42 (d, J=7.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.96 (t, J=7.0 Hz, 1H), 6.81 (s, 1H), 4.42 (s, 2H), 3.01-2.94 (m, 2H), 2.87 (s, 3H), 2.83 (s, 3H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.09-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=505 (MH)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46].CNC>C(Cl)Cl.C1COCC1>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH:29][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: Br
Agent: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N1CC2N(C(=O)C(NS(C)(=O)=O)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2 h

Procedure:
64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were dissolved in 3 ml of DCM. 0.5 mmol of triethylamine and 1.5 equivalents of methanesulfonyl chloride were added to the solution. After 2 hours, 0.5 ml of dimethylamine in THF was added, and the solvent was evaporated in vacuo. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=636.04 (calculated, monoisotopic); measured value (M+H)+: 637.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:78]3[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]3)=[O:30])=[CH:24][CH:23]=2)=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-methylpiperazine (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with DCM/ethanol/ammonia (100:8:1 then 40:8:1), which after evaporation of the solvents under vacuum gave N-{6-methyl-4′-[(4-methylpiperazin-1-yl)carbonyl]-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (14 mg, 29%). NMR; δH [2H6]-DMSO 10.26,(1H, s), 8.19,(1H, d), 7.69–7.67,(2H, m), 7.47–7.41,(4H, m), 7.29,(1H, d), 6.96,(1H, d), 6.86,(1H, s), 3.59,(2H, b), 3.43,(4H, m), 2.33,(6H, b), 2.21,(3H, s), 2.21,(3H, s), 1.95,(4H, m). MS: MH+484.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C.[CH:33]1([C:39]([O:41][CH2:42]I)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(OC(C)C)(C)C>CS(C)=O.CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:42][O:41][C:39]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:40])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reactant: O=C(OCI)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C3CCCCC3)=CCS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.8 %

Procedure:
7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.0 g) was dissolved in a mixed solution of dry dimethylsulfoxide (90 ml) and dry dimethylformamide (30 ml). After adding triethylamine (1.58 g) to the stirred solution at 9° C. over 2 minutes, iodomethyl cyclohexanecarboxylate (4.2 g) was added thereto with stirring over 5 minutes, and then stirred under ice cooling for 35 minutes. Ice water (500 ml) was added to the resultant solution and extracted with ethyl acetate three times. The solution was subsequently washed with a diluted aqueous solution of sodium bicarbonate, an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (100 g) with a mixed solution of chloroform and acetone (10:3). The eluate was evaporated in vacuo to give the purified residue. The residue was pulverized with diisopropyl ether and dried in vacuo to give cyclohexylcarbonyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 4.0 g).
Reaction SMILES: [NH:1]1[C@@H:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3][C:2]1=[O:10].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:14][N:13]=1>>[F:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([N:1]3[C@@H:6]4[CH2:7][CH2:8][CH2:9][C@@H:5]4[CH2:4][O:3][C:2]3=[O:10])=[N:13][CH:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1N[C@@H]2CCC[C@@H]2CO1
Reactant: Fc1cccc(C#Cc2ccc(F)nc2)c1
Product: O=C1OC[C@H]2CCC[C@H]2N1c1ccc(C#Cc2cccc(F)c2)cn1
Yield: 30.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 4 using (4aS,7aR)-hexahydro-cyclopenta[d]-[1,3]oxazin-2-one (66 mg, 0.47 mmol) (Example 1, step 2) and 2-fluoro-5-((3-fluorophenyl)ethynyl)pyridine (100 mg, 0.47 mmol) to yield 48 mg (31%) of the title compound as a light yellow amorphous solid; MS: m/e=337.3 (M+H+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH3:27])[CH:20]=2)=[N:15]1.O.NN>>[NH2:3][C@@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH3:27])[CH:20]=2)=[N:15]1
Reactant: Cc1cc(-c2ccn(C[C@H](C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Agent: NN
Solvent: O
Product: Cc1cc(-c2ccn(C[C@H](C)N)n2)ccc1C#N
Yield: 18.9 %

Procedure:
(S)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (481 mg, 1.3 mmol) was treated with hydrazine hydrate using the method of Example 27(b). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 59 mg (19%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 2.52 (s, 3H), 3.23 (m, 1H), 4.00 (m, 2H), 6.85 (d, 1H), 7.77 (m, 2H), 7.81 (d, 1H), 7.89 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([CH3:23])[CH2:3][CH2:4][C:5]1([CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([Cl:18])[C:9]([Cl:17])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O.C(O)C.[OH-].[Na+]>O>[Cl:17][C:9]1[C:10]([O:15][CH3:16])=[CH:11][C:12]2[CH2:13][CH2:14][C:5]3([CH2:20][CH2:21][CH3:22])[C:6]([C:7]=2[C:8]=1[Cl:18])=[CH:23][C:2](=[O:1])[CH2:3][CH2:4]3
Reactant: CCCC1(CCC(C)=O)CCc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)CC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.7 %

Procedure:
2-(3-Oxobutyl)-7,8-dichloro-6-methoxy-2-propyl-1-tetralone (700 mg), ethanol (25 ml), water (6 ml) and 10N sodium hydroxide solution (200 μl) were combined and stirred at room temperature for 96 hours. The reaction mixture was evaporated in vacuo at 30° C. treated with water, extracted two times with 100 ml of ether, washed with water, brine dried over MgSO4, evaporated in vacuo, and chromatographed on 25 g of SiO2 (ethyl acetate-hexane; 1:2) to give 350 mg of 3,4-Dichloro-6,7,8,8a,9,10-hexahydro-2-methoxy-6-oxo-8a-propylphenanthrene which was used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 25 h
Yield: 90.8 %

Procedure:
To a solution of 6-(benzyloxy)-4-chloro-7-methoxyquinazoline (3.3 g, 0.01097 mol) and 3-aminophenol (1.2 g, 0.01097 mol) in THF (70 mL), Cs2CO3 (5.36 g, 0.0164 mol) was added at room temperature. The reaction mixture was stirred at 75° C. for 25 hr. The mixture was filtered and the solid was washed with ethyl acetate (100 mL). The organic phase was washed with water, brine and dried over MgSO4. The solvent was evaporated under vacuum and the solid was triturated with ethyl ether (20 mL). The solid was filtered and washed with ethyl ether to afford 3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.72 g, 90% yield). 1HNMR (DMSO-d6): δ 8.55 (s, 1H), 7.66 (s, 1H), 7.46 (m, 8H), 7.08 (t, 1H), 6.49 (d, 1H), 6.40 (m, 2H), 5.30 (s, 2H), 4.02 (s, 3H). LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][C:7](=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)C>O.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[Cl:5][CH2:6][C:7](=[O:16])/[C:8](=[N:1]/[OH:3])/[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=N\O)C(=O)CCl
Yield: 91 %

Procedure:
A solution of 35.6 g of sodium nitrite in 100 ml of water was added to a cold solution of t-butyl 4-chloro-3-oxobutanoate (100.9 g, 0.439 moles of 84% material*)inin 400 ml of acetic acid containing 50 ml of water over a 0.5 hour period with stirring. The mixture was stirred in the cold for an additional hour, then stored in the cold overnight. The mixture was diluted with 500 ml portions of water, 500 ml of saturated sodium bicarbonate, 500 ml of water and 500 ml of brine, then dried over magnesium sulfate and evaporated to give an amber oil; yield 88.6 g (91% yield). This material was used in the next step without further purification.