Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH:7]([C:15]([NH:17][S:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)(=[O:20])=[O:19])=[O:16])[C:8](N(CC)CC)=[O:9])=[CH:4][CH:3]=1.Cl.C(OCC)(=[O:36])C>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH:7]([C:15]([NH:17][S:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)(=[O:20])=[O:19])=[O:16])[C:8]([OH:36])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)C(Cc1ccc(Cl)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Product: O=C(O)C(Cc1ccc(Cl)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
To the compound (2.10 g) obtained in Example 110 (4) were added 0.5 mol/L hydrochloric acid (40 ml) and ethyl acetate (80 mL), and the organic layer was collected by partitioning and washed with brine. The organic layer was concentrated under reduced pressure to give the title compound (1.90 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCn1ccc2ccc(Br)cc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Yield: 56.1 %

Procedure:
Following the procedure described in Step 2 of Example 2, 6-bromo-1-ethyl-1H-indole (0.400 g, 1.78 mmol), was coupled to 4-trifluoromethylbenzene boronic acid (0.348 g, 1.83 mmol), using tetrakis(triphenylphosphine) palladium (0.0668 g, 0.0578 mmol), and sodium carbonate (0.769 g, 7.26 mmol) in water (3.6 mL), ethanol (1.5 mL), and toluene (8 mL). Purification by flash chromatography using hexane as an eluant yielded the title compound as a yellow oil (0.289 g, 56%). 1HNMR (300 MHz, DMSO-d6): δ7.95 (d, 2H, J=7.7 Hz), 7.9 (s, 1H), 7.8 (d, 2H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.5 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=7.7 Hz), 6.45 (d, 1H, J=2.3 Hz), 4.3 (q, 2H, J=6.9 Hz) and 1.4 ppm (t, 3H, J=6.9 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]3)[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=3)[C:10]2=[O:14])[C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: O=C1NCCc2cc(C3CC3)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=Cc1c(Br)cccc1N1CCc2cc(C3CC3)ccc2C1=O
Temperature: 110 °C
Yield: 351.1 %

Procedure:
A round bottom flask was charged with 6-Cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one (13.4 g, 5 mmol), 2,6-Dibromo-benzaldehyde (47.5 g, 72.0 mmol), Pd2 (dba)3.CHCl3 (660 mg, 0.72 mmol), xanthphos (832 mg, 1.44 mmol), and cesium carbonate (46.8 g, 144 mmol). The vial was flushed with argon, 140 mL of dioxane was added, and the reaction mixture was heated at 110° C. for 4 h. The reaction mixture was cooled to rt and 30 mL of water and 60 mL of ethyl acetate were added before filtering over Solkaflok. The organic phase was separated and washed with brine followed by drying over Na2SO4. After filtration, the solvent was removed and the brown mass obtained was triturated with methylene chloride and diethyl ether to afford 6.5 grams of 2-Bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzaldehyde. A second crop of 7.5 grams of material was collected by addition of more diethyl ether. MS (ESI) 370.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:23])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[CH3:26][CH:27]([CH3:31])[C:28](Cl)=[O:29].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[C@@H:11]([O:23][C:28](=[O:29])[CH:27]([CH3:31])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6]
Reactant: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 98.8 %

Procedure:
(Ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-hydroxy-3,3-dimethylbutanoate (36b) (0.2 g, 0.49 mmol) was reacted with 0.16 mL (0.16 g, 1.5 mmol) of 2-methylpropanoyl chloride in 5 mL of anhydrous dichloromethane (DCM) in the presence of 0.11 mL (0.11 g, 1.3 mmol) of pyridine. After work-up and isolation, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) and hexane (Hxn) mixtures (EtOAc/Hxn=1:2) as eluent to provide 0.23 g (99% yield) of the title compound (36c) as a colorless oil. Rf=0.55 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.12-1.15 (2s, 3H), 1.21-1.26 (m, 12H), 1.50-1.58 (2d, J=5.2, 5.6 Hz, 3H), 2.30-2.36 (m, 2H), 2.64-2.71 (m, 1H), 3.31-3.36 (m, 2H), 3.69-3.72 (m, 2H), 3.99-4.02 (2d, J=9.2, 9.6 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 4.21-4.28 (m, 2H), 4.75-4.79 (2s, 1H), 6.77-6.82 (m, 1H) ppm. MS (ESI) m/z: 496.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N2CCCC2)c1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Bromo-3-methylbenzoic acid (5.0 g, 23.3 mmol) was dissolved in THF (100 mL) and added N,N′-carbonyldiimidazole (4.52 g, 27.9 mmol). The reaction mixture was stirred at ambient temperature for 14 h. Pyrrolidine (6.8 mL, 81 mmol) was added in one portion. The mixture was stirred for 8 h and then partitioned between EtOAc and water. The organic layer was washed with water, diluted HCl, saturated bicarbonate, water and brine. The solution was then concentrated in vacuo to afford (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone as a white crystalline solid, upon standing overnight at RT.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[NH2:13])=[O:7].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:31]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:10]3[N:11]=[CH:12][C:8]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[C:9]3[N:13]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([CH3:30])(=[O:29])=[O:28])[C:32]#[CH:33]
Reactant: C#CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(C)(=O)=O
Yield: 77.1 %

Procedure:
0.1 g (0.33 mmol) of 4-thiophene-2-carbonyl-2H-pyrazol-3-ylamine and 0.063 g (0.33 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynyl-methanesulfonamide were dissolved in 10 ml of glacial acetic acid. After refluxing for 8 hours, the solvent was removed by reduced pressure distillation. To the resultant residue 10 ml of dichloromethane and 10 ml of a saturated solution of sodium bicarbonate were added. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporate to dryness to yield an oil which, in the presence of ethyl acetate gave a yellow solid, 111 mg (yield=78%) N-2-propynyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-methanesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:30])=[O:29]
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of ethyl 3-amino-4-fluorobenzoate (5.47 g, 30 mmol) and pyridine (2.55 mL, 33 mmol) in DCM (150 mL) was added 2,6-difluorobenzenesulfonyl chloride (4.45 mL, 33 mmol). The reaction was stirred overnight at rt. After 16 h, the reaction mixture was concentrated, triturated with ether, and dried in vacuo to generate 7.87 g (66% yield) of the product of Step A as a white powder. MS (ESI): 360 (M+H).
Reaction SMILES: C[Mg]Br.[CH3:4][C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.[Cl:34][C:35]1[CH:36]=[C:37]([C:41]2[C:46]([O:47][CH:48](F)F)=[CH:45][CH:44]=[C:43]([CH2:51][C:52]3[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=3)[C:42]=2[F:60])[CH:38]=[CH:39][CH:40]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:34][C:35]1[CH:36]=[C:37]([C:41]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[C:43]([CH2:51][C:52]3[CH:53]=[CH:54][C:55]([CH:58]([NH2:59])[CH3:4])=[N:56][CH:57]=3)[C:42]=2[F:60])[CH:38]=[CH:39][CH:40]=1
Reactant: N#Cc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2F)cn1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: C[Mg]Br
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(C(C)N)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 17 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed methylmagnesium bromide (3M in diethyl ether) (1.32 mL, 3.96 mmol), nitrogen in/out lines attached and the solution was cooled to 0-5° C. After the addition of a solution of 5-(3′-Chloro2-fluoro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitrile (P-355, 700 mg, 1.98 mmol) in tetrahydrofuran (10 mL), the reaction was warmed to ambient temperature and stirred for 40 minutes. Additional methylmagnesium bromide (3M in diethyl ether) (660 uL, 1.98 mmol) was introduced and the reaction was heated to 60° C. for 3 hours. The reaction was cooled to 0-5° C. and a slurry of lithium aluminum hydride (150 mg, 3.96 mmol) in tetrahydrofuran (1 mL) was added. The reaction was heated to 60° C. for 1 hour and then partially concentrated, cooled to 0-5° C. and quenched with water (5 mL) and 1M NaOH (3 mL). After the addition of ethyl acetate (10 mL), the reaction was filtered through Celite and the filtrate layers were separated. The aqueous portion was extracted with ethyl acetate (30 mL), the organic portions were combined, dried (MgSO4), concentrated and purified by a 50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 5-40% MeOH/dichloromethane to produce 124 mg of P-606 as a yellow viscous oil in 17% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, J=7 Hz, 3H), 3.72 (s, 3H), 3.94 (s, 2H), 3.99 (q, J=6 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.27-7.29 (m, 1H), 7.32-7.38 (m, 3H), 7.41-7.47 (m, 2H), 7.57 (dd, J=8, 2 Hz, 1H), 8.39 (s, 1H). MS (APCI+): 372.3 (M+2). LC-MS: 95%
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17]3)=[CH:26][N:25]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)N1CCN(c2ccc(N)nc2)CC1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (200 mg, 862 μmol, Eq: 0.95) and 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (200 mg, 908 μmol, Eq: 1.00) in DMF (10.0 ml) was cooled to 0° C. To this reaction mixture was added sodium hydride (116 mg, (60% in mineral oil), 2.9 mmol, Eq: 3.2). The reaction was allowed to stir at 0° C. for 10 min then allowed to warm to room temperature and stir 18 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with water and EtOAc. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 20% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a residue that was placed under high vacuum for 18 h to afford (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-yl]-amine (78 mg, 23%). LC/MS-ESI observed [M+H]+ 372.
Reaction SMILES: C[CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1.OC(C(C)C(O)C(O)C1C=CC=CC=1)CC=CC(O)=O.ClC1C=C(C=CC=1OC)C[C@@H](C(O)=O)N.NCC(C)C(O)=O.C(O)(=O)C(CC(C)C)O.C[C@H]1C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@@H]([C@H]2O[C@@H]2C2C=CC=CC=2)C)CC=CC(=O)N[C@H](CC2C=CC(OC)=C(Cl)C=2)C(=O)NC1.C[C@H]1C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@@H](/C=C/C2C=CC=CC=2)C)CC=CC(=O)N[C@H](CC2C=CC(OC)=C(Cl)C=2)C(=O)NC1.C[C@H]1C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@@H](/C=C/C2C=CC=CC=2)C)CC=CC(=O)N[C@H](CC2C=CC(OC)=CC=2)C(=O)NC1.C[C@@H]1[C@@H](O)[C@H](C2C=CC=CC=2)O[C@H]1C/C=C/C(N[C@@H](C(NC[C@H](C(OC)=O)C)=O)CC1C=CC(OC)=C(Cl)C=1)=O>C(Cl)(Cl)Cl>[CH3:27][C@H:26]([C@H:28]1[O:30][C@@H:29]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:14]1[O:15][C:16](=[O:17])[C@H:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[O:19][C:20](=[O:21])[CH2:2][CH2:3][NH:4][C:5](=[O:6])[C@@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[NH:8][C:9](=[O:10])[CH:11]=[CH:12][CH2:13]1
Reactant: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: CC(C(O)CC=CC(=O)O)C(O)C(O)c1ccccc1
Agent: CC(C)CC(O)C(=O)O
Agent: CC(CN)C(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)CCNC2=O)cc1Cl

Procedure:
[α]D +40.2°(CHCl3 c 0.72); UV λmax (ε) 240 (6700), 280 (2400), 288 (2100); IR (neat) νmax 3403, 3279, 2957, 1731, 1673, 1503, 1464, 1409, 1372, 1258, 1174, 1065, 1023, 889 cm-1 ; EIMS m/z (relative intensity) 640/642 (10/4), 612 (5), 478 (15), 398 (40), 266 (33), 227 (76), 195 (95), 155 (100), 127 (90); high resolution EIMS m/z 640.2550 (calcd for C34H41ClN2O8, 0.2 mmu error); 1H NMR (CDCl3) amino or hydroxy acid unit δ (carbon positions, multiplicities; J in Hz) 7,8-epoxy-5-hydroxy-6-methyl-8-phenyl octanoic acid (A ) 5.73 (2, d; 15.4), 6.68 (3, ddd; 15.0, 9.9 and 4.9), 2.45 (4, m), 2.56 (4, m), 5.19 (5, ddd; 11.2, 5.1 and 1.5), 1.80 (6, m), 1.14 (6-Me, d; 7.1), 2.92 (7, dd; 7.5 and 2.0), 3.68 (8, d; 1.8), 7.25 (10/14, m), 7.33-7.38 (11/12/13, m); 3-chloro-4methoxyphenylalanine (B) 4.74 (2, ddd; 8.2, 6.8 and 6.2), 5.68 (2-NH, d; 8.6), 2.98 (3, dd; 14.3 and 7.7), 3.14 (3, dd; 14.3 and 5.6), 7.21 (5, d; 2.0), 3.86 (7-OMe, s), 6.83 (8, d; 8.4), 7.07 (9, dd; 8.4 and 2.0); 3-aminopropionic acid (C) 2.56 (2, m), 3.51 (3, m), 3.45 (3, m), 6.90 (3-NH, br t; 5.8); leucic acid (D) 4.89 (2, dd; 10.0 and 3.3), 1.67 (3, m), 1.31 (3, m), 1.67 (4, m), 0.84 (5, d; 6.4), 0.83 (5', d; 6.4); 13C NMR (CDCl3) unit δ (carbon position) A 165.5 (1), 125.3 (2), 141.0 (3), 36.7 (4), 75.9 (5), 40.6 (6), 13.5 (6-Me), 63.0 (7), 59.0 (8), 136.7 (9), 125.6 (10/14), 128.7 (11/13), 128.5 (12); B 170.7 (1), 53.9 (2), 35.0 (3), 129.8 (4), 130.9 (5), 122.4 (6), 153.9 (7), 56.1 (7-OMe), 112.2 (8), 128.3 (9); C 172.6 (1), 32.4 (2), 34.4 (3), D 170.5 (1), 71.2 (2), 39.5 (3), 24.4 (4), 22.8 (5), 21.2 (5').
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[F:53][C:54]1[CH:55]=[C:56]2[C:60](=[CH:61][CH:62]=1)[CH2:59][NH:58][CH2:57]2>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:58]1[CH2:57][C:56]2[C:60](=[CH:61][CH:62]=[C:54]([F:53])[CH:55]=2)[CH2:59]1)=[O:6]
Reactant: Fc1ccc2c(c1)CNC2
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)Cl)c(Cl)c2)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CC(C)N1CCC(Oc2ccc(C(=O)N3Cc4ccc(F)cc4C3)c(Cl)c2)CC1
Reaction time: 16 h
Yield: 70 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D33) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline hydrochloride (D8) (0.10 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E63) as a white solid (0.09 g). MS electrospray (+ion) 417/419 (MH+). 1H NMR δ (DMSO-d6): 9.80 (1H, s), 7.22-6.81 (6H, m), 4.70-4.39 (3H, m), 4.25 (3H, m), 3.24 (2H, m), 2.88 (2H, m), 2.10-1.70 (4H, m), 1.06 (6H, m).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CO.C1COCC1>[C:12]([C:8]1[N:7]=[C:6]2[C:11]([C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]2[CH3:18])=[CH:10][CH:9]=1)#[CH:13]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(C#C[Si](C)(C)C)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2n1
Temperature: 23 °C
Reaction time: 23 h

Procedure:
To a solution of 2-(4-hydroxy-1-methyl-2-oxo-7-(2-(trimethylsilyl)ethynyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetic acid (183 mg, 490 μmol, Example 19 (b)) in MeOH (5 mL) and THF (5 mL) was added potassium carbonate (339 mg, 2450 mmol), and the reaction mixture was stirred at 23° C. for 23 hours. The mixture was acidified with concentrated HCl, and filtered. The filter cake was washed with water (10 mL), Et2O (10 mL) and DCM (10 mL), and dried in vacuo to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 302 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.22-10.52 (m, 1 H), 8.43 (d, J=8.0 Hz, 1 H), 7.54 (d, J=8.2 Hz, 1 H), 4.74 (s, 1 H), 4.14 (d, J=5.5 Hz, 2 H), 3.64 (s, 3 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:22]=[N:21][CH:20]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].IC.[CH3:37]COC(C)=O.CCCCCC>CN(C=O)C.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:37])[C:10]([N:12]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH:22]=[N:21][CH:20]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: CCCCCN(Cc1cncn1Cc1ccc(C#N)cc1)C(=O)Nc1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCN(Cc1cncn1Cc1ccc(C#N)cc1)C(=O)N(C)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of urea 1 (remaining half of crude product prepared above) in 1 mL of dry DMF at 0° C. was added NaH (14 mg, 60% dispersion in mineral oil). After 15 minutes, iodomethane (0.029 mL) was added dropwise. The reaction was stirred at 0° C. for four hours, then poured into EtOAc/hexane (2:1) and water, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a purple oil. This material was purified by silica gel chromatography (2-5% MeOH/CH2Cl2), taken up in CH2Cl2 and treated with 1 M HCl/ether solution, and concentrated in vacuo. The product hydrochloride 8 (22 mg) was isolated as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:26]1[CH2:25][CH:24]1[CH2:22][N:17]1[CH2:16][CH2:15][N:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1
Reactant: BrCC1CO1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CC3CO3)CC2)cc1
Temperature: 25 °C
Reaction time: 100 h

Procedure:
A solution of 4,4'-difluorobenzhydrylpiperazine (28.83 g, 100 mmol) in acetonitrile (250 mL) was added to an ice cold mixture of epibromohydrin (9.1 mL, 110 mmol) and anhydrous potassium carbonate (15.2 g, 110 mmol) in acetonitrile (150 mL) over a period of 40 min. The mixture was stirred at room temperature for 100 h, filtered and the solids were washed with methylene chloride. The combined filtrates were concentrated to dryness to give an oil which was eluted through a flash chromatographic silica gel column using 2-3% methanol/methylene chloride to give the title compound as glass, 23.98 (69.6%); 300 MHz 1H NMR (CDCl3):δ 7.4-6.9 (m, 8H). 4.22 (s. 1H). 3.09 (br m, 1H), 2.8-2.25 (m, 12H); MS 345 (MH+).
Reaction SMILES: [CH2:1]([CH:4]1[C:8]([OH:10])([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(Cl)(=O)C>O.ClCCl>[CH2:1]([CH:4]1[C:8]([O:10][C:20](=[O:21])[CH2:19][Cl:18])([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C=CCC1C(=O)C=CC1(C)OC(=O)CCl
Reaction time: 3 h
Yield: 90.6 %

Procedure:
Into the same flask as in Example 1, dl-2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), pyridine (15 g) and dichloromethane (150 g) were charged, and chloroacetyl chloride (22.5 g) was dropwise added thereto at a temperature from 10° to 15° C. in 3 hours. Then, stirring was continued at room temperature for 24 hours. To the reaction mixture kept below 10° C., water (50 ml) was added to decompose excess of acetyl chloride. The resulting mixture was treated as in Example 1. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate (10:1) as an eluent to give dl-2-allyl-3-chloroacetyloxy-3-methyl-4-cyclopentenone (20.7 g). Yield, 91%.