Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30]C(=O)C)[CH:10]=1.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30][S:37]([CH:34]2[CH2:36][CH2:35]2)(=[O:39])=[O:38])[CH:10]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)cn1

Procedure:
The compound was prepared from the compound of Example 1 using the procedures of Example 2 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.88 (s, 1H), 8.23 (s, 1H), 8.0 (s, 1H), 7.96 (s, 1H), 7.76-7.64 (m, 3H), 7.6 (s, 2H), 7.5-7.46 (m, 2H), 7.3-7.25 (m, 1H), 3.88 (s, 3H), 2.88-2.85 (m, 1H), 1.02-1.0 (m, 4H); LC-MS (ESI): Calculated mass: 505.54; Observed mass: 506.1 [M+H]+ (rt: 1.517 min).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10][NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCc1oc2ccccc2c1CNc1ccc(O)cc1
Reaction time: 24 h

Procedure:
At ambient temperature, to a stirred solution containing 2-n-butylbenzofuran-3-carboxaldehyde (0.888 g, 4.77 mmol) and 4-aminophenol hydrochloride in MeOH (7 mL) was added sodium cyanoborohydride (0.330 g, 5.25 mmol). After 24 h, the reaction was carefully quenched with 3N HCl, diluted with H2O and extracted with CH2Cl2. The organic extracts were washed with sat. aq. NaHCO3, dried and concentrated. Purification on silica gel eluting with a 20 & 40% EtOAc/pet. ether step gradient gave the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 0.93 (t, 3 H), 1.38 (sextet, 2 H), 1.70 (quintet, 2 H), 2.79 (t, 2 H), 4.27 (s, 1 H), 4.35 (br. s, 1 H), 6.62 (d, 2 H), 6.75 (d, 2 H), 7.18-7.26 (m, 3 H), 7.41 (d, 1 H), 7.54 (d, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:17][O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[F:28].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:29])=[C:22]([F:28])[CH:23]=2)[CH:9]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cccc(C(C)(C)C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)c(F)c2)c1

Procedure:
Following General Procedure B and using 2-(3-ethynyl-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate 132, 0.10 g, 0.46 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.136 g, 0.46 mmol), triethyl amine (8 mL), copper(I)iodide (0.01 g, 0.05 mmol) and dichlorobis(triphenylphosphine)-palladium(11) (0.035 g, 0.05 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.15 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][CH2:23][NH:24][S:25]([NH2:28])(=[O:27])=[O:26])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].C(O)(=O)C>CO>[NH2:28][S:25]([NH:24][CH2:23][CH2:22][CH2:21][NH:20][C:16]1[C:15]([C:10](=[N:11][OH:12])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=2)=[N:19][O:18][N:17]=1)(=[O:26])=[O:27]
Reactant: NS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)NCCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A solution of N-[3-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)propyl]sulfamide (35 mg, 73 μmol) in methanol (1 mL) was treated with 2 M NaOH (0.3 mL, 0.6 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with acetic acid (50 μL, 0.9 mmol), filtered, and purified by preparative LCMS to give the desired product (14 mg, 42%) as a solid. LCMS for C12H16BrFN7O4S (M+H)+: m/z=451.8, 453.9. 1H NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 8.89 (s, 1H), 7.17 (dd, J=8.8, 8.6 Hz, 1H), 7.09 (dd, J=6.1, 2.7 Hz, 1H), 6.76-6.72 (m, 1H), 6.56 (dd, J=6.1, 6.1 Hz, 1H), 6.51 (s, 2H), 6.17 (dd, J=5.9, 5.9 Hz, 1H), 3.27-3.21 (m, 2H), 2.94-2.88 (m, 2H), 1.78-1.71 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=2)[N:8]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (42 mg, 0.156 mmole) and p-trifluoromethylbenzoyl chloride (32.5 mg, 0.156 mmole) were combined in 3 ml of methylene chloride (CH2Cl2), treated with triethylamine (0.0157 g, 0.156 mmole) and stirred at room temperature 15 minutes. The mixture was diluted with CH2Cl2 (20 ml), washed with 10% citric acid (2×5 ml), dilute sodium bicarbonate (2×5 ml), and water (2×5 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate (0.4 ml)/ether (1 ml) to give the title compound which was dried in vacuo at 90°: (m.p. 209°-211°).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([CH2:60][NH2:61])=[CH:56][CH:55]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35].CN1CCOCC1>CN(C)C=O>[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([CH2:60][NH:61][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=4)=[CH:58][CH:59]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CN)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CNC(=O)c3cccc(O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
3-Hydroxy-benzoic acid (27 mg, 0.19 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) were added to a solution of 3-[3-(4-aminomethyl-benzylcarbamoyl)-pyridin-2-yloxy]-benzoic acid ethyl ester hydrochloride (100 mg, 0.19 mmol) (see Preparation 9) and N-methyl morpholine (0.11 ml, 0.97 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours, concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was then purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:1, by volume) giving 3-(3-{4-[(3-hydroxy-benzoylamino)-methyl]-benzylcarbamoyl}-pyridin-2-yloxy)-benzoic acid ethyl ester (45 mg) as an off-white foam.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O-].[Na+].CO.CI>CS(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Oc1cccnc1Br
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CS(C)=O
Product: COc1cccnc1Br
Temperature: 90 °C
Reaction time: 20.5 h

Procedure:
100.0 g (corresponding to 0.575 mol) of 2-bromo-3-hydroxypyridine was dissolved in 310 mL of dimethylsulfoxide, and 575 mL (corresponding to 0.575 mol) of a 1 mol/L sodium methoxide-methanol solution was added thereto. Then, the reaction solution was heated to 90° C. to distill off methanol. After the reaction solution was cooled down to 10° C. or lower, 93.9 g (corresponding to 0.662 mol) of methyl iodide was added, and then stirred at room temperature for 20.5 hours. After the completion of the reaction, the reaction solution was poured into ice water and extracted twice with chloroform. The combined chloroform layer was washed with a 1 mol/L sodium hydroxide solution, washed twice with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, 65.4 g (corresponding to 0.348 mol) of 2-bromo-3-methoxypyridine was obtained (FIG. 3, Step 1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].Cl.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [Na]
Product: COc1ccc(N2CCN(c3ccc(S(=O)(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino}-propionic acid, sodium salt and 4-(4-methoxy-phenyl)-piperazine dihydrochloride were condensed to give the title compound as a brown solid, mp=203-205° C.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=O.C[O-].[Na+].[C:10](Cl)(=O)[CH3:11].C([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#C>CC(N(C)C)=O.O>[CH2:5]([C:4]1[CH:19]=[C:20]([C:21]2[CH:16]=[N:17][CH:18]=[CH:10][CH:11]=2)[O:3][N:1]=1)[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCC[N+](=O)[O-]
Reactant: C#Cc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1cc(-c2cccnc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.45 g (5 mmole) nitropropane and 5 ml 1N (5 mmole) sodiummethoxide was dissolved in dry dimethylacetamide (25 ml). To this solution 0.39 g (5 mmole) acetylchloride and 0.51 g (5 mmole) 2-ethynylpyridine was added. The reaction mixture was stirred overnight at room temperature. Water (150 ml) was added, and the solution extracted with 3×30 ml ethylacetate. The organic phase was dried over magnesiumsulphate and concentrated in vacuo giving 3-(3-ethyl-5-isoxazolyl)pyridine in a 500 mg yield. This compound was quartarnized with methyliodide and reduced with sodiumborohydride as described above giving the title compound in a 170 mg yield. M.p. 169°-170° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:45])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyl-oxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichloro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (360 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stiffed for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 80% ethyl acetate in isohexane, to afford the product (395 mg, 57.5%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 2.54 (3H, s), 3.09-3.13 (2H, m), 3.16-3.21 (1H, m), 3.29-3.34 (1H, m), 3.87-3.92 (2H, m), 4.51 (1H, qn), 5.92-5.95 (1H, m), 7.43-7.47 (1H, m), 7.52-7.55 (2H, m), 8.14 (1H, d), 8.41 (1H, s), 8.59 (1H, s), 9.42 (1H, d), 9.96 (1H, s); m/z (ES+) (M+H)+=631; HPLC tR=2.94 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][NH:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH2:17][N:4]1[C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][O:5]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)CONC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1(C)CON(Cc2ccc(F)cc2Cl)C1=O
Yield: 30.3 %

Procedure:
A solution of 0.52 grams (0.005 mole) of 4,4-dimethyl-3-isoxazolidinone, 1.0 gram (0.005 mole) of (2-chloro-4-fluorophenyl)methyl bromide and 0.62 gram (0.005 mole) of potassium carbonate in 40 ml of dimethylformamide was stirred at ambient temperature for 18 hours. The dimethylformamide was removed under high vacuum with mild heat. The residue was extracted with methylene chloride. The extract was filtered and dried with sodium sulfate. The mixture was refiltered and the filtrate concentrated under reduced pressure to give an oil residue. The residue was slurried in warm hexane and a solid was removed by filtration. The filtrate was concentrated under reduced pressure to give 0.39 gram of 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:78])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[NH:74][CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:63][CH2:62][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:60][CH2:59]1>CN(C=O)C>[F:78][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[N:74]([C:4](=[O:6])[C@@H:3]([O:2][CH3:1])[CH3:7])[CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:59][CH2:60][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:62][CH2:63]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: CO[C@@H](C)C(=O)O
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@@H](C)C(=O)N1Cc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CC1C
Reaction time: 2 h

Procedure:
A solution of (S)-2-methoxypropanoic acid (1.9 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (90 μL) was stirred at room temperature for 10 min then treated with N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) 6 ppm 1.17 (t, J=6.7 Hz, 1.4H), 1.27 (dd, J=6.7, 2.7 Hz, 1.6H), 1.33 (dd, J=11.5, 6.7 Hz, 1.4H), 1.38 (dd, J=6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.58 (m, 0.6H), 2.64 (m, 0.4H), 2.95-3.05 (m, 2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.44 (m, 2H), 3.71-3.86 (m, 2H), 4.03 (t, J=18.3 Hz, 1H), 4.30-4.41 (m, 1H), 4.43-4.50 (m, 1H), 4.70-4.83 (m, 1H), 5.08 (m, 0.5H), 5.21 (m, 0.5H), 5.89-6.21 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 525.9.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[C:12](=[O:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1>[CH:1]1([C:6]2[C:15]([C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)=[O:27])=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[CH:12]([OH:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)c(F)c2)C1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2.1 g (4 mmol) of 2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-3-(4 trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one were dissolved in 20 ml of tetrahydrofuran and, at 0° C., added dropwise to a solution of 0.2 g (1.2 mmol) of 1R,2S-aminoindanol and 2.7 ml (16 mmol) of boranediethylaniline complex in 2 ml of THF. The mixture is stirred at RT overnight. After about 20 hours, the reaction was quenched using 2.4 ml of 1,2-ethanediol. The tetrahydrofuran was distilled off, the resulting oil was taken up in ethyl acetate and the organic phase was, after washing with 2N hydrochloric acid and saturated sodium bicarbonate solution, dried and concentrated. The residue was recrystallized from hot cyclohexane. This gave a total of 1.4 g of colourless crystals of melting point: 166-168° C.
Reaction SMILES: [CH3:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)Cl)CC1
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C(=O)n2ccnc2)CC1
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 1-methylcyclopropylcarbonyl chloride (11.8 g) in toluene (15 ml) was added dropwise to a solution of imidazole (13.6 g) in tetrahydrofuran (100 ml) whilst maintaining the temperature below 25° C. The mixture was stirred for 3 hours and filtered. The filtrate was evaporated to dryness to give 1-(1-methylcyclopropylcarbonyl)-imidazole (13.6 g) as a white solid, mp 34°-35° C.
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:54][CH3:55])[CH:11]([CH3:53])[CH:12]1[O:52][CH:13]1[CH2:14][CH:15]([CH3:51])/[CH:16]=[CH:17]/[CH:18]=[C:19](\[CH3:50])/[CH:20]1[O:32][C:30](=[O:31])[CH2:29][CH:28]([O:33][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:27][CH2:26][C:25]([O:42][CH:43]([O:45][CH2:46][CH3:47])[CH3:44])([CH3:41])[CH:24]([OH:48])[CH:23]=[CH:22][CH:21]1[CH3:49])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.ClC(O[C:76]1[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=1)=O.[C:85]([O:88]CC)(=[O:87])C>C(Cl)Cl>[C:1]([O:9][CH:10]([CH2:54][CH3:55])[CH:11]([CH3:53])[CH:12]1[O:52][CH:13]1[CH2:14][CH:15]([CH3:51])/[CH:16]=[CH:17]/[CH:18]=[C:19](\[CH3:50])/[CH:20]1[O:32][C:30](=[O:31])[CH:29]([C:85]([OH:88])=[O:87])[CH:28]([O:33][Si:34]([CH2:35][CH3:36])([CH2:39][CH3:40])[CH2:37][CH3:38])[CH2:27][CH2:26][C:25]([O:42][CH:43]([O:45][CH2:46][CH3:47])[CH3:44])([CH3:41])[CH:24]([O:48][C:76]2[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=2)[CH:23]=[CH:22][CH:21]1[CH3:49])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)C=CC1O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)C(C(=O)O)C(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)/C=C/C1Oc1ccc([N+](=O)[O-])cc1
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)/C=C/C1O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)C(C(=O)O)C(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)C=CC1Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(8E,12E,14E)-21-benzoyloxy-6-(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (57.1 mg, 72.7 μmol) was dissolved in methylene chloride (0.5 mL). Triethylamine (51.0 μL, 366 μmol) and dimethylaminopyridine (4.9 mg, 40.1 μmol) was added to the solution, and the reaction solution was cooled to 0° C. A solution of 4-nitrophenyl chloroformate (45.0 mg, 223 μmol) in methylene chloride (0.5 mL) was added to the solution. The reaction solution was warmed to room temperature and stirred for five hours. 4-Nitrophenyl chloroformate (17.8 mg, 88.3 μmol) was further added to the reaction solution, and the solution was stirred at the same temperature for two hours. The reaction solution was diluted with ethyl acetate (30 mL), and the dilution was washed with saturated aqueous solution of sodium hydrogencarbonate (10 mL) twice, purified water (10 mL) twice, and brine (10 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=9:1) to obtain the title compound (106.6 mg) as a mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CCN(C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1
Reactant: OC1CCNCC1
Reactant: Fc1cncc(Cl)c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OC1CCN(c2c(F)cncc2Cl)CC1
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-5-fluoro-4-iodo-pyridine (1 g, 3.885 mmol) in NMP (1 mL) was added DIPEA (753.1 mg, 1.015 mL, 5.828 mmol) and piperidin-4-ol (589.4 mg, 5.828 mmol) and the mixture heated to 120° C. for 4 hours. The mixture was diluted with ethyl acetate (30 ml), washed twice with water (20 ml) and with brine. The organic layer was dried with MgSO4 and concentrated in vacuo to a yellow solid that was purified by column chromatography using DCM and then 2% MeOH/DCM as eluent, yielding 1-(3-chloro-5-fluoro-4-pyridyl)piperidin-4-ol. MS (ES+) 231.0.