Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:3]=1)=[O:15]
Reactant: NCCNc1ccccn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCNc3ccccn3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl)2-pyridinylamine (88 mg, 0.64 mmol) were suspended in 2 mL of NMP and irradiated (microwave) as follows: 180° C. for 30 min, 200° C. for 30 min, 220° C. for 30 min, 230° C. for 30 min and then 240° C. for 1 h. After cooling to room temperature, some of the solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 90:10:1). The collected solid was partitioned between water and EtOAc/toluene (1:1) and then extracted twice with DCM/isopropanol. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to afford a dark brown oil. After drying under vacuum overnight, the residue was again purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH (gradient 0 to 90:10:1). The collected solid was suspended in EtOH, sonicated, and filtered. The solid was further washed with EtOH/DCM, filtered, and dried in vacuum-oven for 2 days. The final product was collected as 47 mg (45%). LCMS E-S (M+H)=475.0 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1 H) 8.47 (t, J=5.05 Hz, 1 H) 7.97 (dd, J=4.93, 1.14 Hz, 1 H) 7.85 (s, 1 H) 7.32-7.39 (m, 2 H) 6.65 (s, 1 H) 6.61 (t, J=5.43 Hz, 1 H) 6.46-6.51 (m, 2 H) 5.89 (s, 1 H) 4.97 (quin, J=6.69 Hz, 1 H) 4.32 (d, J=5.05 Hz, 2 H) 3.49 (dt, J=15.28, 5.62 Hz, 4 H) 2.21 (s, 3 H) 2.13 (s, 3 H) 1.44 (s, 3 H) 1.43 (s, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:21]([O:22][CH3:23])=[C:20]3[C:15]([C:16](=[O:45])[C:17]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][C:34]=4[CH3:44])=[O:30])=[CH:18][N:19]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:14][C:13]=2[F:46])[CH2:7]1)C.O1CCOCC1.[Li+].[OH-].Cl>C(OCC)(=O)C>[F:46][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([O:22][CH3:23])[C:12]=1[N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([CH2:5][C:4]([OH:47])=[O:3])[CH2:7]1)[N:19]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH:18]=[C:17]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:35][C:34]=1[CH3:44])=[O:30])[C:16]2=[O:45]
Reactant: CCOC(=O)C[C@@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1c(N2CCC[C@@H](CC(=O)O)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Yield: 101 %

Procedure:
72 mg (0.107 mmol) of the compound of Example 20 are stirred with 2.6 ml of dioxane and 533 μl of LiOH (1M solution in water, 5 eq.) at RT overnight. The mixture is acidified with 1N HCl and diluted with ethyl acetate. It is extracted by shaking twice with water and once with a saturated NaCl solution. The organic phase is dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under HV. 70 mg of the title compound (99% of theory) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[Li]CCCC.[CH3:29][O:30][C:31]1([CH3:42])[C:36]([O:38][CH3:39])([CH3:37])[O:35][C@@H:34](C#N)[CH2:33][O:32]1>C1COCC1>[CH3:39][O:38][C:36]1([CH3:37])[C:31]([O:30][CH3:29])([CH3:42])[O:32][C@@H:33]([C:19]2[NH:18][C:16](=[O:17])[C:15]3[C:14]([C:13]=2[C:4]2[C:5]([CH3:12])=[C:6]4[C:11](=[C:2]([F:1])[CH:3]=2)[O:10][CH2:9][CH2:8][CH2:7]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:34][O:35]1
Reactant: COC1(C)OC[C@H](C#N)OC1(C)OC
Reactant: CNC(=O)c1ccccc1Cc1cc(F)c2c(c1C)CCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1(C)OC[C@H](c2[nH]c(=O)c3ccccc3c2-c2cc(F)c3c(c2C)CCCO3)OC1(C)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
An ice cooled suspension of 2-((8-fluoro-5-methylchroman-6-yl)methyl)-N-methylbenzamide (300 mg, 0.957 mmol) in THF (5 mL) was treated with 2.5M nBuLi in hexanes (804 μl, 2.010 mmol). Upon addition of the n-BuLi, the reaction became homogeneous and dark red in color. After 10 min, a solution of (2S)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbonitrile (289 mg, 1.436 mmol) in THF (0.5 mL) was added and the colorless solution was maintained at 0° C. for 5 min. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO (0-10% MeOH-DCM) to afford the title compound (408 mg, 0.844 mmol, 88% yield) as a 1:1 mixture of diastereomers as a pale yellow foam. LC/MS (m/z) ES+=484 (M+1). Rt=2.17, 2.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([NH:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[OH-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[NH:7][C:5](=[O:6])[C:4]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
3,4-Dichlorobenzoyl-2-tert-butylhydrazine (5.63 g, 0.0215 mole) is added to a rapidly stirring mixture of 40 mL of methylene chloride and 20 mL of 10% aqueous sodium hydroxide (2 g, 0.05 mole). Benzoyl chloride (d=1.211, 2.5 mL, 3.03 g, 0.0215 mole) in methylene chloride is added and the reaction mixture stirred vigorously for approximately three hours at ambient temperature. The resulting solid is collected and washed with water and methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)=[O:8].[Br:24]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:24][C:11]1[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:2]([Cl:1])[CH:3]=2)=[O:8])[C:18]([OH:19])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1ncc2cccnc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Reaction time: 4 h

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide from Example 1, Step 3 (1.28 g, 3.69 mmol) in CH2Cl2 (100 ml) at room temperature was added N-bromosuccinimide (0.689 g, 3.87 mmol). The reaction was stirred for 4 hrs and then poured into water. The organic phase was washed with water (3×100 ml), and dried (Na2SO4). The solvent was evaporated in vacuo and the residue triturated with CH2Cl2 to afford the title compound as an off white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([F:15])=[C:10]([Cl:16])[N:9]=1>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]([F:15])=[C:10]([Cl:16])[N:9]=1
Reactant: C1COCCN1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: CCO
Product: Fc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A solution of morpholine (1.5 mL, 17.05 mmol) in ethanol (25 mL) was added to a cooled (−20° C.) solution of 2,4,6-trichloro-5-fluoropyrimidine (3.00 g, 14.93 mmol) in ethanol (150 mL) and the resulting mixture was stirred at −20° C. for 30 minutes and at ambient temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene chloride. The organic layer was separated, dried and the solvent evaporated under reduced pressure. The resulting white solid was triturated with ethanol, then filtered and dried to give the title compound (2.0 g, 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (0.300 g, 0.86 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.356 g, 1.029 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 24%). MS (ISP) 532.1 [(M+H)+]; mp 225° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH3:13][P:14]([CH3:23])([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:15].Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:23][P:14]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])=[CH:18][CH:17]=1)([CH3:13])=[O:15]
Reactant: C=Cn1cnc2c(Cl)ncnc21
Reactant: CP(C)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 160 °C

Procedure:
A mixture of 6-chloro-9-vinylpurine (0.18 g, 1 mmol), 4-dimethylphosphinylaniline (0.17 g, 1 mmol), and pyridine hydrochloride (0.11 g, 1 mmol) was dissolved in 2-ethoxyethanol (2 mL). The resulting solution was heated at 160° C. for 10 minutes under microwave irradiation. The mixture was concentrated to dryness on a rotavap. EtOAc and aq. NaHCO3 were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (eluent: 10% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: O[CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][N:6]2[CH2:9][CH2:10][CH2:11][C:12]([CH3:23])([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH3:13])[CH2:3]1.[C-:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1.C(P(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl>C(#N)C>[C:24]([CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][N:6]2[CH2:9][CH2:10][CH2:11][C:12]([CH3:23])([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH3:13])[CH2:3]1)#[N:25]
Reactant: [C-]#N
Reactant: CC(C)(CCCN1CC2CC(O)C1C2)S(=O)(=O)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(CCCN1CC2CC(C#N)C1C2)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
6-Hydroxy-2-[4-methyl-4-(phenylsulfonyl)pentyl]-2-azabicyclo[2.2.1]heptane (1 g, 2.97 mmol), potassium cyanide (386 mg, 6 mmol) and 18-crown-6 (78 mg, cat.) were suspended in acetonitrile and the mixture was cooled in ice-water. Tri-n-butylphosphine (1.2 ml, 5 mmol) was added followed by dropwise addition of carbon tetrachloride (0.57 ml, 6 mmol). The mixture was allowed to stir at room temperature for 12 h. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica using a gradient elution of 10–100% ethyl acetate in i-hexane, to give the product (600 mg, 58%) as an oil which crystallised on standing.
Reaction SMILES: C(OCC([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=O)C(=C)C.[CH2:16]([O:20]C1C=CC(N)=CC=1)[C:17](=[CH2:19])[CH3:18]>>[CH2:16]([O:20][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[NH2:9])[C:17](=[CH2:18])[CH3:19]
Reactant: C=C(C)COc1ccc(N)cc1
Reactant: C=C(C)COCC(=O)Nc1ccccc1
Product: C=C(C)COc1cccc(N)c1

Procedure:
The starting material was meta-methallyloxyacetamidobenzene, which was obtained under the same conditions as those described in Example 4, paragraph (4.1) for paramethallyloxyacetamidobenzene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[N:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCc2ccccc21
Temperature: 80 °C
Yield: 73.2 %

Procedure:
Indoline (1.07 g, 8.98 mmol), ethyl bromoacetate (1.20 ml, 10.8 mmol), potassium carbonate (2.10 g, 15.2 mmol) were added to dimethylformamide (14 ml), and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and then washed with water and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as yellow oil (1.35 g, yield: 73%).
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li+].[OH-].[ClH:30]>C1COCC1.O>[Cl:30][CH2:25][C:21]1[CH:20]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:27])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][CH:22]=1
Reactant: Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CO)c4)ccnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CCl)c4)ccnc32)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of compound G″ in THF, water was added LiOH (3.68 g, 0.087 mol) at rt and stirred for 4 h at same temperature. The reaction mixture was concentrated to obtain residue which was diluted with water (50 ml), acidified with 2N aq. HCl solution, adjusted to pH=5-6, the precipitated solid was filtered, washed with water and dried (traces water were removed by co-evaporating with toluene) to obtain compound H″. The compound H″ was washed with diethyl ether to obtain desired purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:30](=[O:41])[C:29]=1[C:42](Cl)=[O:43])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH:13][C:42]([C:29]3[C:30](=[O:41])[N:31]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[CH:32]=[CH:33][C:28]=3[O:27][CH2:25][CH3:26])=[O:43])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of Example A2 (29 g, 113 mmol) and triethylamine (23 g, 226 mmol) in THF (400 mL) was added freshly prepared 4-ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (33.5 g, 113 mmol) and the mixture was stirred at RT overnight. The mixture was concentrated in vacuo, and the residue was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (51 g, 87% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][O:25]C(=O)C)[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:32]([O:34]C)=[O:33])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][OH:25])[CH2:10][C@H:9]1[C:32]([OH:34])=[O:33])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)COC(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Methyl (2S,4S)-1-BOC-4-{[3-(acetoxy)-2,2-dimethylpropanoyl] (4,4-dimethylcyclohexyl)amino}pyrrolidine-2-carboxylate (0.88 g, 1.77 mmol) obtained in Step A was dissolved in MeOH (8 mL) and water (1.6 mL). NaOH (213 mg, 5.31 mmol) was added thereto. The reaction solution was stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, acidified with 1N HCl and extracted with EtOAc. The extracted organic solution was washed with 1N HCl solution, dried over MgSO4 and concentrated in vacuo to give the title compound (0.74 g, 95%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]2([CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:5]1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][N:5]1[C:4](=[O:3])[C:9]2([CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@H:6]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)NC(=O)C12COCCOC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 mg (0.55 mmol) sodium hydride were added to 0.18 g (0.5 mmol) (3R)-tert-butyl 5-oxo-3-phenyl-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 3 ml DMF. After 5 min at RT 54 μl (0.91 mmol) methyl bromoacetate were added and then the reaction mixture was stirred for 1 h at RT. The reaction was poured onto ice water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cnco1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cnco2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1%-4% methanol in dichloromethane, 145 mg (80%) of the desired compound. 1H NMR (CDCl3) δ0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.39-1.50 (m, 2H), 1.80-1.94 (m, 1H), 2.56-2.74 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.52-3.62 (m, 1H), 3.72-3.84 (m, 1H), 3.88-3.92 (m, 1H), 4.08-4.35 (m, 3H), 4.62 (d, J=6Hz, 1H), 4.94 (s, 2H), 5.91 (d, J=8.4 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.06-7.26 (m, 11H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.35 (s, 1H). Mass spectrum: (M+NH4)+ =706; (M+H)+ =689. Anal. Calcd for C37H48N6O7.0.5 H2O: C, 63.68; H, 7.08; N, 12.04. Found: C, 63.50; H, 7.13; N, 11.60.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:29]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCOC(COc3ccccc3Cc3cccs3)C2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOC(COc2ccccc2Cc2cccs2)C1
Yield: 85.7 %

Procedure:
To a solution of 3.8 g of 4-benzyl-2-[2-(2-thenyl)phenoxymethyl]-morpholine in 30 ml of toluene was added 1.2 g of ethyl chloroformate, and the mixture was heated under reflux for 6 hours. After cooling, the insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give 3.1 g of crude 4-ethoxycarbonyl-2-[2-(2-thenyl)-phenoxymethyl]morpholine as an oil. The oil was dissolved in 40 ml of ethanol, and a solution of 3.2 g of barium hydroxide in 50 ml of water was added, and the mixture was heated under reflux for 8 hours. After cooling, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The remaining oil was extracted with two 70 ml portions of 5% hydrochloric acid, and the combined water layer was made alkaline with sodium hydroxide. The liberated oil was extracted with benzene, and the benzene extract was dried over potassium carbonate. Then the benzene was distilled off to give 1.6 g of 2-[2-(2-thenyl)phenoxymethyl]-morpholine as an oil. A solution of the oil (1.6 g) in 15 ml of isopropyl ether was added to a solution of 0.65 g of maleic acid in 7 ml of ethanol to give 2.1 g of colorless crystals. The crystals were recrystallized from a mixture of methanol and isopropyl ether (1:1) to give 1.5 g of 2-[2-(2-thenyl)phenoxymethyl]morpholine maleate as colorless crystals, melting at 155°-156° C.