Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:15]=[C:14]([C:16]2[C:17]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:18][N:19]([C:21]3[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)[CH:20]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C([O:39]C(NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3N=NC(Cl)=CC=3)C=2)C=CN=1)=O)(C)(C)C>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:17]2[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH3:8])[CH:15]=3)=[CH:20][N:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:39])[NH:23][N:22]=3)[N:18]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Reactant: CC(C)(C)OC(=O)CNc1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Product: CNc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccc(F)cc2)ccn1
Yield: 89 %

Procedure:
The reaction was carried out in the same manner as in Example 2-4) except for using 330 mg (0.69 mmol) of 4-{2-[(t-butoxycarbonyl)methylamino]pyridin-4-yl}-1-(6-chloropyridazin-3-yl)-3-(4-fluorophenyl)-1H-pyrazole obtained in Example 3-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(6-chloropyridazin-3-yl)-3-(4-fluorophenyl)-1H-pyrazole to obtain 222 mg of the title compound as a pale beige powder. (Yield: 89%)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1>CO.[C].[Pd]>[F:22][C:2]([F:1])([F:23])[C:3]1[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncccc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ncccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was purged and maintained with an inert atmosphere of hydrogen, was added a solution of tert-butyl 4-(3-(trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (449.3 mg, 1.27 mmol, 1.00 equiv, 93%) in methanol (20 mL) and Palladium carbon anhydrous (134.8 mg). The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 379.8 mg (87%) of tert-butyl 4-(3-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate as colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.CO>C(OCC)C>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cccc(-n2ccnc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: OCc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
230 mg of 1-(3-ethoxycarbonylphenyl)imidazole see J. Am. Chem. Soc., 79, 4922 (1957)1 was dissolved in ml of ethyl ether, and 50 mg of lithium aluminium hydride was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration. The solvent was evaporated and then the residue was purified by silica gel column chromatography Wakogel C-200, 20 g; eluting solvent: chloroform/methanol=20/1) to give 160 mg (yield 92%) of the captioned compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cccc(F)c1F
Product: CCOC(=O)C(C)=NNc1cccc(F)c1F

Procedure:
The title compound, EI-MS: m/e=242.1 (M+), was prepared in accordance with the general method of example 25b) from 2,3-difluorophenyl hydrazine and ethyl pyruvate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:33])[C:19]([OH:32])([C:24]3[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:34])[C:13]=2[Cl:35])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[Cl:35][C:13]1[C:14]([Cl:34])=[C:15]([CH:18]([CH3:33])[C:19]([OH:32])([C:24]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[CH:25]=2)[C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2cnc(C(=O)O)cn2)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
5-{2,3-Dichloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-propyl]-phenoxy}-pyrazine-2-carboxylic acid methyl ester (Example 237; 160 mg, 0.3 mmol) in 1.2 ml THF was treated with 0.6 ml 1N aqueous NaOH and stirred at rt for 2 h. After addition of 1 ml 1N HCl, the reaction mixture was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo to give 156 mg of the title compound as a white solid. MS (M+H+)=518.1
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)c1nccc(N2CCC[C@@H](O[Si](C)(C)C(C)(C)C)C2)c1N
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (R)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding (R)-3-amino-6-bromo-N-(4-(3-(tert-butyldimethyl-silyloxy)piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:28]1([CH:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(CC)CC>CN(C=O)C.O>[CH:34]([NH:35][C:8]([C:7]1[C:2]([OH:1])=[N:3][C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:5][CH:6]=1)=[O:10])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(-n2cccn2)nc1O
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
4-Hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid (1-1-a, 8 g, 38.8 mmol) and CDI (7.24 g, 44.6 mmol) was dissolved in DMF (80 mL), stirred for 45 min at 105° C., then cooled to 77° C. Diphenylmethanamine (9.2 g, 50.4 mmol) and Et3N (5.41 ml, 38.8 mmol) were then added to the solution at 77° C. and the reaction mixture was stirred for 5 h. The resulting mixture was cooled to ambient temperature, diluted with 150 ml of water, extracted with ethyl acetate (3 times 150 ml). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, purified by recrystillized in EtOH/Et2O (1/10). A yellow solid was obtained as product, 1-1-b, (6.4 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 6.32-6.34 (d, J=8.4, 1H), 6.50-6.51 (m, 1H), 7.29-7.43 (m, 11H), 7.74 (s, 1H), 8.55-8.58 (m, 2H), 11.77 (s, 1H). LC-MS 372 [MH]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH3:22][O:23][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28].CC([O-])=O.[Na+]>O.CO>[CH2:5]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][N:1]=[C:26]([C:25](=[O:31])[CH2:24][O:23][CH3:22])[C:27]([O:29][CH3:30])=[O:28])=[C:15]([F:20])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1F
Reactant: COCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=O)C(=NNc1ccc(OCc2ccccc2)cc1F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
A solution of NaNO2 (2.07 g, 30 mmol) in H2O (5 mL) was added dropwise at 0° C. to a mixture of 4-(benzyloxy)-2-fluoroaniline (5.43 g, 25 mmol) and 6 M HCl aqueous solution (25 mL, 150 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (3.24 mL, 24 mmol) and NaOAc (12.3 g, 150 mmol) in MeOH (50 mL) pre-cooled at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (8.48 g, 91% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.500 (3H×0.46, s), 3.502 (3H×0.54, s), 3.88 (3H×0.54, s), 3.92 (3H×0.46, s), 4.65 (2H×0.46, s), 4.68 (2H×0.54, s), 5.06 (2H×0.54, s), 5.07 (2H×0.46, s), 6.75-6.86 (2H, m), 7.32-7.44 (5H, m), 7.53 (1H×0.46, t, J=9.0 Hz), 7.76 (1H×0.54, t, J=9.0 Hz), 13.12 (1H×0.46, brs), 15.13 (1H×0.54, brs).
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:9]1[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:23]C)[C:13]([O:21]C)=[N:14]2)[CH2:6][CH:7]=[CH2:8])(=[O:4])=[O:3].Cl>O1CCOCC1>[CH3:1][S:2]([CH:5]([C:9]1[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=[C:15]2[C:10]=1[NH:11][C:12](=[O:23])[C:13](=[O:21])[NH:14]2)[CH2:6][CH:7]=[CH2:8])(=[O:3])=[O:4]
Reactant: C=CCC(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C=CCC(c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12)S(C)(=O)=O
Temperature: 90 °C
Yield: 67.8 %

Procedure:
A mixture of 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenyl methyl sulphone (from step (a), 27 mg, 0.069 mmol), 2M hydrochoric acid (0.5 ml) and dioxane (1 ml) was warmed at 90° C. for 15 h, cooled and concentrated under reduced pressure. The residue was sonicated with ether and a few drops of methanol and the resulting white solid was collected by filtration, washed with ether and dried to afford the title compound (17 mg, 68%) as a white powder, m.p. 270.5-272° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].N1CCO[CH2:9][CH2:8]1.[CH:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:26][CH2:27]OCC>>[CH2:17]([CH:16]1[CH2:27][CH2:26][C:13](=[O:25])[CH2:14][CH2:15]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCC=O
Reactant: CCOCC
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74 %

Procedure:
A mixture of potassium carbonate (1 equivalent) and morpholine (3.3 equivalents) were cooled to -5° under an inert atmosphere and dodecanal (1 equivalent) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for 3-6 hours. Addition to ether followed by filtration and concentration gave crude morpholine enamine. The residue was distilled to give the desired product; b.p. 103-108° /0.07 mm; yield 74%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:13][C:14]([C:16]2([NH:34]C(=O)OC(C)(C)C)[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[C:30]([CH:31]5[CH2:33][CH2:32]5)=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1>O1CCOCC1.CO>[NH2:34][C:16]1([C:14]([NH:13][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][OH:12])=[O:15])[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[C:30]([CH:31]4[CH2:32][CH2:33]4)=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
Hydrogen chloride 4M in dioxane (0.923 mL, 3.69 mmol) was added to (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 65) (420 mg, 0.74 mmol) in dioxane (25 mL). The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was dissolved in methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (25.0 mg, 7.2%) as a white solid.
Reaction SMILES: Br[CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].[NH3:30].Cl>ClCCCl.C(OCC)(=O)C>[NH2:30][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4]
Reactant: N
Reactant: CC(Br)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(N)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Reaction time: 0.5 h
Yield: 64 %

Procedure:
23.04 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine was dissolved in 65 ml of 1,2dichloroethane and 65 ml of ethyl acetate, into which ammonia gas was passed at -15° C. for 1 hour. This solution was placed in a sealed tube and reacted at 110° C. for 2 hours. In order to complete the reaction, ammonia was again passed into the solution at -15° C. for 30 minutes in the sealed tube where the reaction was continued at 110° C. for 1.5 hours. After ice-cooling, the reaction solution was charged into ice-cooled 2N hydrochloric acid, to which ethyl acetate was added, from which the resultant aqueous phase was collected. Sodium carbonate was added to the aqueous phase under ice-cooling conditions so that the pH was adjusted to 8, followed by extraction with chloroform under salting-out conditions. The extract was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. followed by filtration and concentration to obtain 12.97 g (yield 64%) of the intended compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=NC2C(Br)=CC=CC=2Br)[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:28]=1[NH2:29].C(C1C(O)=C(C=C(C(C)(C)C)C=1)C=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=[N:29][C:28]2[C:27]([Cl:26])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:34])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)c1cc(C=Nc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C=Nc2c(Cl)cccc2Cl)c(O)c(C(C)(C)C)c1

Procedure:
An analogous procedure was employed to that described above for the synthesis of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)imino]methyl]phenol, using 2,6-dichloroaniline (1.03 g, 6.4 mmol) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde (1.5 g, 6.4 mmol). The product was purified by recrystallisation from hot ethanol and the product isolated as yellow crystals. Yield 1.87 g, 77%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:15])[NH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO.O>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:3][NH:4][C:5]2=[O:15])=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Br)c[nH]c(=O)c2cc1F
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: COc1cc2c(N3CCOCC3)c[nH]c(=O)c2cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-7-fluoro-6-methoxyisoquinolin-1(2H)-one (0.5 g, 1.838 mmol) and morpholine (0.4 g, 4.59 mmol) in ethylene glycol (2.5 ml) was added DIPEA (1.031 ml, 5.90 mmol). The reaction was irradiated in microwave at 145° C. for 1.5 h. The reaction was cooled to ambient temperature and diluted with water. The aqueous layer was extracted with EtOAc. The organic layer was washed with 1N HCl, followed by washing with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get the crude compound. The crude compound (0.25 g, 31.8%) was taken to the next step without further purification. MS: MS m/z 279.22 (M++1).
Reaction SMILES: Br[C:2]1[C:11]([O:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:7]2.[Cl:30]C1C(O)=CC=C2C=1C=CC([C@]1(C)COC(=O)N1)=C2>>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:11]2[C:2]([Cl:30])=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:5]=[CH:4]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Reactant: C[C@@]1(c2ccc3c(Cl)c(O)ccc3c2)COC(=O)N1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Cl)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 213) in 57% yield using (R)-4-(5-chloro-6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one as the to starting material.
Reaction SMILES: O1CCCC1.[CH2:6]([NH:13][C:14](=O)[C:15]1[C:16](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>CO>[CH2:20]([NH:19][CH2:17][C:16]1[C:15]([CH2:14][NH:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCNC(=O)c1ccccc1C(=O)NCCCCCCC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNCc1ccccc1CNCCCCCCC
Yield: 12.9 %

Procedure:
To a 1M solution of borane-tetrahydrofuran complex (24 ml) was added dropwise under ice cooling a 5 ml tetrahydrofuran solution containing 3.6 g of N,N'-diheptylphthalamide obtained in Example 2 under an argon gas stream, and the mixture was warmed up slowly and then heated under reflux for one hour. After cooling, 2 ml methanol was added dropwise under ice cooling, and the mixture was heated under reflux for 30 minutes. After cooling in ice, 4.24 ml concentrated hydrochloric acid was added, and the mixture was again heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was basified by addition of an aqueous solution of caustic soda and extracted with chloroform. After distilling off the chloroform from the extract, the residue was purified by silica gel column chromatography, giving 0.43 g of N,N'-diheptyl-o-xylylenediamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:54])([O:51][CH2:52][I:53])[O:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>C(#N)C>[I-:53].[CH2:44]([O:43][C:41]([CH2:40][CH2:39][CH2:38][O:37][C:36]([O:51][CH2:52][N:33]1[CH2:34][NH+:30]([CH2:29][C@@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:35])[C@H:10]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[N:26][N:25]=[N:24]4)=[CH:19][CH:18]=3)[C:13]2=[O:28])[CH3:11])[N:31]=[CH:32]1)=[O:54])=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(CCCOC(=O)OCI)OCc1ccccc1
Solvent: CC#N
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)OCCCC(=O)OCc2ccccc2)C=N1)c1ccc(F)cc1F
Product: [I-]
Reaction time: 20 h
Yield: 82.1 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (1.0 g) in acetonitrile (15 ml) was added (3-benzyloxycarbonylpropyl) iodomethyl carbonate (1.0 g) under a nitrogen atmosphere, and the mixture was stirred for 20 hours at 45-50 C. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate→acetone ), and a fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2) to give 4-[(3-benzyloxycarbonylpropoxy)carbonyloxymethyl]-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium iodide (Compound 32, 1.47 g) as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=[O:44].CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][C:40]3=[O:44])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: NCCN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN3CCCC3=O)n2)s1
Temperature: 50 °C
Yield: 68 %

Procedure:
A mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.28 mmol), 1-(2-aminoethyl)-2-pyrrolidinone (0.18 g, 0.83 mmol) and DIEA (0.10 ml, 0.56 mmol) in MeOH (0.5 ml) was heated at 50° C. for 2 h. LCMS analysis indicated that the reaction was proceeding very slowly, another equivalent amine and DIEA was added and the reaction was heated overnight. LCMS analysis indicated the reaction had still not progressed sufficiently so the reaction was heated overnight again. LCMS analysis indicated the reaction had progressed sufficiently so the reaction mixture was concentrated onto silica gel and purified by flash chromatography to afford a colourless foam. The product was dissolved in DCM and washed with HCl (10% Aq.) to remove some residual DIEA and the organics were dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford the title compound (0.12 g, 67% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.22-7.65 (m, 7H), 3.21-3.45 (m, 6H), 2.11-2.22 (m, 2H), 1.82-1.93 (m, 2H), 1.41 (s, 9H). MS (ES+): 631 [M+H]+.