Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)nc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g) was dissolved in methylene chloride (9.6 ml), and a solution of m-chloroperbenzoic acid (130 mg) in methylene chloride (6.4 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-pyridinylmethyl)sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 270) (180 mg).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)cc1
Yield: 20.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (85 mg, 0.155 mmol) was deprotected in TFA/toluene (2.5/5 ml). This afforded 14 mg (20.2% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.576-8.571 (d, 1H), 8.46-8.45 (d, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.73-7.71 (m, 3H), 7.48-7.46 (d, 2H), 7.25-7.20 (m, 2H), 7.14-7.07 (m, 3H), 7.48-7.43 (t, 2H), 3.56-3.52 (d, 2H), 3.22-3.15 (m, 4H), 3.07-2.98 (dt, 1H), 2.17-2.13 (d, 2H), 2.06-1.91 (m, 2H). MS: m/z=448.4 (M+1), HPLC: 91.78% in method B.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][OH:23])=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C:21]1[C:16]([O:15][C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:8]=[N:9][C:10]=3[C:2]=2[Br:1])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:34])=[O:33]
Reactant: OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2-{[4-bromo-1-(cyclopropylmethyl)-1H-1,2,3-benzotriazol-5-yl]oxy}pyridin-3-yl)methanol (195) (1 g, 2.62 mmol, 1.0 equiv.) and Et3N (1.1 ml, 7.85 mmol, 3.0 equiv.) in DCM (13 ml) were cooled to 0° C., followed by MsCl (265 ul, 3.40 mmol, 1.3 equiv.), then stirred @ 0° C. for 1 hour. The reaction mixture then quenched with NaHCO3(sat) and extracted with DCM (2×40 ml). The combined DCM layer was washed with brine and dried over Na2SO4, filtered and concentrated down solvent. LRMS m/z (M+H) 486.8 and 488.8 found, 487.0 and 489.0 required.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.C(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C1(CCc2cccs2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccs3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-21; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.2 mmol), potassium carbonate (4 mmol) in DMF (3 mL). The product was isolated via flash chromatography over silica gel using 10:90 EtOAc:CH2Cl2, mp 73-77° C. MS (APCI): 475 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:10]O)=[N:4][CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]([CH3:9])=[CH:5][N:4]=1
Reactant: Cc1cnc(CO)c(C)c1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cnc(CBr)c(C)c1C

Procedure:
The compound was obtained from reacting (3,4,5-trimethyl-pyridin-2-yl)-methanol with triphenyl phosphine and carbon tetrabromide in dichloromethane as described in the general procedure 2.5. HPLC Rt: 3.979 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 4.63 (s, 2H), 2.35 (s, 3H), 2.48 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: BrC1C(OC)=CC=C(C=1)C=[O:8].[N+](CC)([O-])=O.C(N)CCC.[N+]([C:25]([CH3:36])=[CH:26][C:27]1[CH:28]=[C:29]([Br:35])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])([O-])=O.Cl>C1(C)C=CC=CC=1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.[Fe]>[Br:35][C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([CH2:26][C:25](=[O:8])[CH3:36])[CH:28]=1
Reactant: COc1ccc(Br)cc1C=C(C)[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1Br
Agent: Cl[Fe](Cl)Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC[N+](=O)[O-]
Product: COc1ccc(Br)cc1CC(C)=O
Temperature: 75 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
A mixture of 5-bromoanisaldehyde (19.4 g, 90 mmol), toluene (25 ml), nitroethane (8.1 g, 108 mmol) and butylamine (2.0 g, 27 mmol) was vigorously refluxed under heating while removing water generated by the reaction with a Dean-Stark distilling tube. During the reflux, N-butylamine (4.5 ml) and nitroethane (4 ml) were added in several portions and the reaction proceeded for 6 hr. Then, the reaction mixture was cooled and extracted with toluene and 3N hydrochloric acid. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give a brown oil containing 3-(2-nitropropen-1-yl)-4-methoxybromobenzene. The oil was dissolved in toluene (30 ml) and an aqueous solution (30 ml) of iron(III) chloride hexahydrate (1.0 g) was added. Thereto was added iron powder (15.1 g, 270 mmol) and the mixture was heated to 75° C. While vigorously stirring the mixture, concentrated hydrochloric acid (37.5 ml, 450 mmol) was dropwise added over 2 hr. After the dropwise addition, the mixture was stirred for 1 hr at 75° C. After cooling, the insoluble matter was filtered off and the filtrate was partitioned. The aqueous layer was extracted with toluene. The organic layers were combined, washed with 3N hydrochloric acid, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give the objective compound (6.9 g, 33%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:5][C:4]([CH:12]=O)=[N:3]1.[Cl-].[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH2:25][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:24]=[C:20]2[C:19]([CH3:45])=[N:18][CH:17]=1>>[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH:25]=[CH:12][C:4]3[N:5]=[C:6]([N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[N:2]([CH3:1])[N:3]=3)[N:24]=[C:20]2[C:19]([CH3:45])=[N:18][CH:17]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(C=O)nc1N1CCCC1
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N4CCCC4)n(C)n3)nc12
Yield: 39.5 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 1-methyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole-3-carbaldehyde (45 mg, 250 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (115 mg, 250 μmol, Eq: 1.00) as starting materials. Chromatography afforded 5,8-Dimethyl-2-[2-(1-methyl-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyrazine (32 mg, 39.5%) as white solid. MS: m/z=325.5 (M+H+)
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:6].Cl.N[OH:23]>C(O)C>[OH:6][C:5]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[O:23][N:2]=[CH:3][CH2:4]1
Reactant: NO
Reactant: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C1(O)CC=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 449 %

Procedure:
A mixture of 3-dimethylamino-1-(2-nitro-4-trifluoromethylphenyl)-prop-2-en-1-one (41.0 g) and hydroxylamine hydrochloride (1 1.9 g) in dry ethanol (280 ml) was stirred at room temperature overnight. It was evaporated to dryness and the residue was dissolved in a mixture of ether (150 ml) and water (100 ml). The layers were separated and the organic layer was washed with water (100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit (bp 60°-80° C.) (20 ml) and filtered to give 5-hydroxy-5-(2-nitro-4-trifluoromethylphenyl)-isoxazoline (33.9 g) as a pale yellow solid mp 122°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[OH-].[K+]>O.NN>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ncccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Cc1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of oxo-(1H-pyrrolo[2,3-b]-pyridine-3-yl)-acetic acid methyl ester (0.300 g, 1.47 mmol) is refluxed in hydrazine monohydrate (10 mL) for 1 hour to give a solution. KOH pellets (0.300 g, 5.35 mmol) are added and reflux is continued for 1 hour. The reaction mixture is evaporated to dryness in vacuo. To the residue is added dry MeOH (10 mL) and the solution is cooled in an ice bath. Concentrated H2SO4 (0.5 mL) is carefully added and the reaction mixture is refluxed at 80° C. for 1 hour. The reaction mixture is evaporated to dryness in vacuo, then partitioned between saturated NaHCO3 aqueous and EtOAc. The EtOAc layer is separated and the aqueous phase is extracted with a further portion of EtOAc. The organics are combined, dried (Na2SO4) and evaporated in vacuo. The crude product is purified by flash chromatography with a pre-packed Isolute™ silica column, eluting with 1:8 EtOAc/iso-hexane-neat EtOAc gradient to afford (1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid methyl ester; MH+=191.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[BH4-].[Li+].O.CO>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
Ethyl(2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (300 mg) was dissolved in tetrahydrofuran (10 mL), lithium tetrahydroborate (29 mg) was added under ice-cooling, and the mixture was stirred at 50° C. for 30 min. To the reaction solution was added lithium tetrahydroborate (29 mg), and the mixture was stirred at 50° C. for 2.5 hr. Furthermore, lithium tetrahydroborate (29 mg) was added, and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate:hexane=0:90:10 to 10:90:0, volume ratio) to give the title compound (150 mg, yield 54%) as a pale-yellow amorphous solid. The amorphous solid was crystallized from ethyl acetate-diethyl ether-hexane, and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound as pale-yellow crystals.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][C@H:23]1[C:28]([O:30][CH3:31])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16].[C:32]1(O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][C@H:23]1[C:28]([O:30][CH3:31])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 0.1 %

Procedure:
DIAD (4.13 ml, 21.0 mmol) was added to a solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.69 g, 19.1 mmol), phenol (1.98 g, 21.0 mmol) and triphenylphosphine (5.51 g, 21.0 mmol) in THF (80 ml) under stirring at room temperature in a nitrogen gas stream. The reaction mixture was stirred overnight at room temperature. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by chromatography on a silica gel column (silica gel: 700 g), whereby from chloroform/ethyl acetate (10/1) eluate fractions, the title compound (5.31 mg, 86%) was obtained as a colorless oil.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]([CH2:26][OH:27])[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35]([O:2][CH2:3][CH:4]([CH2:26][O:27][C:35](=[O:36])[NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH2:7][N:6]2[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)N(Cc1ccccc1)CC2
Reactant: O=C=Nc1ccccc1
Agent: Cl
Product: COc1cc2c(cc1OC)C(C(COC(=O)Nc1ccccc1)COC(=O)Nc1ccccc1)N(Cc1ccccc1)CC2

Procedure:
0.01 mole of the compound obtained in Step (A) is boiled with 0.02 mole of phenyl isocyanate for 4 to 6 hours. Evaporation of the reaction mixture yields the aimed compound in a crystalline form.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@@H:11]1[NH:16][C:15](=O)[CH2:14][O:13][CH2:12]1)[CH:8]([CH3:10])[CH3:9]>C1COCC1>[CH2:7]([C@H:11]1[CH2:12][O:13][CH2:14][CH2:15][NH:16]1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C[C@H]1COCC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C[C@H]1COCCN1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC(O)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 95 °C

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 314c (176 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatri-cyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (198 mg, 0.50 mmol), Pd(dppf)Cl2 (41 mg, 0.050 mmol), K3PO4 (212.0 mg, 1.0 mmol), sodium acetate (82.0 mg, 1.0 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 1 hour. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford crude 314d as a brown solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 623.8.
Reaction SMILES: B.C1COCC1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C1COCC1>CO>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A borane-THF complex (1.08 M THF solution) 23 mL was added dropwise to a mixture of 3.02 g of tert-butyl 4-[3-(4-nitrophenyl)propanoyl]piperazine-1-carboxylate and THF 40 mL under ice cooling in an argon atmosphere, followed by stirring for 10 minutes at room temperature, and then heating under reflux was performed for 2 hours. The reaction mixture was cooled with ice, and 30 mL of methanol was added dropwise thereto, followed by stirring for 3 hours at 50° C. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/chloroform), thereby obtaining 2.78 g of tert-butyl 4-[3-(4-nitrophenyl)propyl]piperazine-1-carboxylate.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21]>CO>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A 5N aqueous solution of NaOH (4 mL, 20 mmol) was added into a solution of methyl 2-chloro-2′-(trifluoromethyl)biphenyl-4-carboxylate (1.07 g, 3.40 mmol) in MeOH (16 mL) and stirred at RT for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was taken up with EtOAc and washed with a 1N aqueous solution of HCl (3×) and brine, and then dried (MgSO4) and concentrated under vacuum to give the title compound as a white powder (950 mg, 93%). HPLC (Method A) Rt 4.9 min (Purity: 99.4%). LC/MS (Method B): 299.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.48 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.94 (dd, J=7.9, 1.6 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.78 (m, 1H), 7.69 (m, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H).