Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 243.1, 80 mg, 0.173 mmol), pyrimidin-5-ylboronic acid (42.9 mg, 0.347 mmol), Pd(PPh3)2Cl2 (12.16 mg, 0.017 mmol) and Na2CO3 (73.5 mg, 0.693 mmol) were added to a MW vial and treated with a mixture of DME (735 μL), water (210 μL) and EtOH (105 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 15 min, diluted with DCM (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 72.2 mg, 0.104 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH+1% NH4OH from 1% to 10% MeOH+1% NH4OH). Product was further purified by preparative SFC (Column DEAP, isocratic 6% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=461.1 [M+H]+, m/z=459.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.81 (m, 1H) 1.82-1.94 (m, 1H) 2.68 (d, J=9.66 Hz, 1H) 2.98-3.10 (m, 2H) 3.18-3.27 (m, 1H) 4.17-4.26 (m, 1H) 4.89 (d, J=3.55 Hz, 1H) 6.99 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.90 (m, 3H) 7.95 (dd, J=8.80, 2.20 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].O[C:13]1[CH:20]=CC(C=O)=C[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:14][CH2:13][CH3:20])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Product: CCCOc1c(Cl)cc(C=O)cc1Cl
Yield: 94 %

Procedure:
When 3,5-dichloro-4-hydroxybenzaldehyde was substituted for 4-hydroxy-benzaldehyde in Example 50, Step A the similar procedure afforded the title compound in 94% yield, as pale oil. 1H-NMR (CDCl3) 1.1 (tr, 3H, J=7.41 Hz); 1.82-1.93 (m, 2H); 4.04 (tr, 2H, J=6.54 Hz); 7.8 (s 2H); 9.84 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:12][C:11]=2[C:31]([O:33][CH2:34][CH2:35]Br)=[O:32])=[CH:6][CH:5]=1.C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:12]3[CH2:35][CH2:34][O:33][C:31](=[O:32])[C:11]=23)=[CH:6][CH:5]=1
Reactant: COc1cc(/C=C/c2nc(C(=O)OCCBr)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCOC3=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.2 %

Procedure:
Sodium hydride (containing mineral oil at 60%, 3 mg) was added to a solution of 2-bromoethyl 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylate (27 mg) in DMF (2 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 27 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C1(COC(=O)[NH:10][C@@H:11]([CH3:20])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)C=CC=CC=1>[Pd].CO>[NH2:10][C@@H:11]([CH3:20])[C:12]([NH:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[O:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)Nn1cccc1
Yield: 89.3 %

Procedure:
The CBZ group of (S)-phenylmethyl-[1-methyl-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (5.50 g) was cleaved in a minimal volume of methanol over 5% Pd-C (0.83 g) with H2 (g) (468 ml) under atmospheric conditions. The catalyst was removed by filtration through a pad of celite and the filter cake was washed with methanol. The combined filtrate was concentrated and the residue purified via flash column chromatography (silica gel, 20% EtOH/ethyl acetate) to afford 2.62 g of the desired product as an oil which crystallized on standing, m.p. 81°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](C)[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:23](=[O:24])[CH2:22][O:21][CH2:20][C:11]=3[NH:12][C:13]3[CH2:18][O:17][C:15](=[O:16])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(C)c(Br)c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2C3=C(COCC3=O)NC3=C2C(=O)OC3)cc1Br
Temperature: -10 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
The product from Example 68A (0.63 g, 1.6 mmol) in chloroform (10 mL) under a nitrogen atmosphere was treated with pyridine (0.16 mL, 1.9 mmol) and pyridinium tribromide (0.57 g, 1.8 mmol) at −10° C. After stirring at −10° C. for 2 hours, the mixture was allowed to warm to ambient temperature and then was treated with 1M HC1 and extracted with chloroform. The chloroform layer was dried (MgSO4), filtered, concentrated, heated to 130° C. under nitrogen for 1 hour and cooled to ambient temperature. Purification of the residue by chromatography on silica gel eluting with 10% methanol in dichloromethane provided the title compound (0.30 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].I[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:17])[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: Cc1ccc(NS(C)(=O)=O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(C)(=O)=O)cc1Br
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A solution of N-(3-bromo-4-methylphenyl)methanesulfonamide (Intermediate 196, step 1; 710 mg; 2.69 mmol) in anhydrous DMF (14 mL) was treated with NaH (129 mg; 3.23 mmol) followed after 5 minutes by treatment with iodomethane (200 μl; 3.23 mmol). The reaction mixture was stirred for 16 hours, then quenched with a 5 N solution of NaOH in water. The reaction mixture was stirred for few minutes and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4 and concentrated to dryness affording the title compound as a brown sticky solid (730 mg, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:9](O)(=[O:11])C>CO.C[O-].[Na+]>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:11][CH3:9]
Reactant: N#Cc1cnccn1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cnccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 910.8 %

Procedure:
Cyanopyrazine (5.26 g, 50 mmol) was dissolved in methanol (40 ml), and sodium methoxide (0.27 g, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes. After the reaction was completed, acetic acid (0.33 g, 5.5 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl pyrazinecarboximidate (6.87 g) as colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]([C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:21]([C:19]1[CH:18]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:20]=1)[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[N:10])([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(OCc2ccccc2C#N)cc(C(C)(C)C)c1

Procedure:
Using the method of Example 1, 20.6 g (0.10 mole) of alpha-bromo-o-tolunitrile was reacted with 3,5-di-t-butylphenol to give 9.9 g of white crystalline 2-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile.
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Cl:24][CH:2]([Cl:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1)[OH:7])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 22.5 °C

Procedure:
(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIIa) (60.5 g, 0.1519 moles) selectively hydrolyses in methylene chloride (300 mL) and water (100 mL) containing p-toluene sulfonic acid at 60° C. over several hours. Removal of the methylene chloride by distillation and cooling to 20-25° C. precipitates the product. Filtration, washing with water (100 mL) and toluene (100 mL) then drying yields (1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol (Florfenicol).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][CH:38]=[N:37]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][CH2:35][N:36]5[CH:40]=[CH:39][CH:38]=[N:37]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: CNCCCn1cccn1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCCn1cccn1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(3-pyrazol-1-yl-propyl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-(3-pyrazol-1-yl-propyl)-amine following General Procedure B.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1)(=O)C.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[NH2:4][C:5]1[N:14]=[C:13]([O:30][CH:27]([CH3:29])[CH3:28])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:11]=2)[N:6]=1
Reactant: CC(C)O
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(-c3ccc(F)cc3)ccc2n1
Product: CC(C)Oc1nc(N)nc2ccc(-c3ccc(F)cc3)cc12
Yield: 85 %

Procedure:
This compound, synthesized from 2-acetamido-6-(4-fluorophenyl)-4-(1,2,4-triazolyl)-quinazoline and isopropanol in 85% yield using the same procedure as in example 18, was characterized by its mass spectrum as follows: MS (m/z): 283 ([M+H]+, 100).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:20]=[C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:22]=1[Br:23])[C:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:14]2[O:15][C:18]([CH3:19])=[CH:17][N:16]=2)[CH:20]=[C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:22]=1[Br:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CCNC(=O)c1cc(OCOCC[Si](C)(C)C)c(Br)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc(-c2cc(OCOCC[Si](C)(C)C)c(Br)c(OCc3ccccc3)c2)o1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Sodium hydride (0.953 g, 39.7 mmol) was added to a solution of 3-(benzyloxy)-4-bromo-N-(prop-2-ynyl)-5-((2-(trimethylsilyl)ethoxy)-methoxy)benzamide (6.49 g, 13.2 mmol) in dioxane (100 mL) and the mixture was heated at reflux overnight. The solution was cooled to room temperature and quenched by slow addition of saturated NaHCO3. The solution was diluted with ethyl acetate/diethyl ether and washed with water (5×), saturated NaHCO3, brine, dried over sodium sulfate and concentrated to a thick brown liquid. Flash chromatography (80 g silica gel, 5-40% EtOAc in heptane) provided 2-(3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazole as an orange oil (3.33 g). MS (M+1)=492.21. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30-7.58 (m, 7H), 6.86 (d, J=1.0 Hz, 1H), 5.40 (s, 2H), 5.25 (s, 2H), 3.80-3.92 (m, 2H), 2.41 (s, 3H), 0.95-1.04 (m, 2H), 0.02 (s, 10H).
Reaction SMILES: Cl.[S:2]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])(=[O:4])[NH2:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CCN(CC)CC>>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:11]2[CH2:12][CH2:13][C:8]3([C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:6]([S:2](=[O:4])(=[O:5])[NH2:3])[CH2:7]3)[CH2:9][CH2:10]2)=[O:31])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: NS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(N)(=O)=O)c2ccccc23)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a suspension of 1-sulfamoylspiro[indoline-3,4′-piperidine] hydrochloride 3-1 (100 mg, 0.33 mmol) and phenyl 4-acetylphenylcarbamate 3-2 (92 mg, 0.36 mmol) in CHCL3 (3 mL) was added Et3N (0.23 mL, 1.65 mmol) at room temperature. The reaction mixture was heated to reflux for 1 h. The resulting suspension was cooled to room temperature. The resulting suspension was filtered and the filter cake was washed with CHCl3 to give 300 (47 mg, 33%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[O:30]C(=O)[O:28][C:27]2=O)=[CH:22][CH:21]=1>C1COCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:27](=[O:28])[CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[OH:30])[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)C(O)c1ccc(F)cc1
Temperature: 63 °C
Yield: 63 %

Procedure:
To a solution of 2-amino-4-(benzyloxy)benzamide (4.0 g, 16.5 mmol) in THF (60 mL) was added a solution of 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione (3.65 g, 18.6 mmol) from Example 16 in THF (20 mL) portionwise at rt. After heating to 63° C. for 18 h, the solution was cooled and concentrated. After addition of H2O, the solution was extracted twice with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. Chromatography on silica gel eluting with 10 to 80% EtOAc/DCM afforded 4-(benzyloxy)-2-(2-(4-fluorophenyl)-2-hydroxyacetamido)benzamide as a foamy solid (4.1 g, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.06 (m, 1H), 5.12 (s, 2 H) 6.68-6.74 (m, 1H) 7.14-7.20 (m, 2 H) 7.32-7.51 (m, 6 H) 7.77 (d, J=8.85 Hz, 1 H) 8.05 (br. s., 1 H) 8.30 (d, J=2.64 Hz, 1 H) 12.73 (s, 1 H). LC-MS (ESI) m/z 392 (M−2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[NH4+].[Cl-]>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:15]
Reactant: COc1cccc([Mg]Br)c1
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
3-Methoxyphenyl magnesium bromide (1.0 M solution in THF; 5.4 mL, 5.4 mmol) was taken in a flask under N2 and cooled (0° C.). 2-Bromobenzaldehyde (1 g, 5.4 mmol) in anhydrous THF (10 mL) was added dropwise via syringe over 5 min. The reaction mixture was stirred at this temperature for 20 min. and slowly brought to room temperature. After stirring for another 30 min. satd. NH4Cl solution (20 mL) was added and the mixture was extracted with Et2O (3×25 mL). The combined Et2O extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The oil was purified by mplc using CH2Cl2 as eluent to give 1.275 g (81%) of the alcohol as a colorless oil. 1H NMR (CDCl3)d: 2.71 (s, 1H, OH), 3.78 (s, 3H, CH3), 6.15 (s, 1H, CH), 6.80-7.58 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 55.80, 75.16, 113.29, 119.90, 123.39, 128.33, 129.11, 129.71, 130.08, 133.39.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[O:23][C:22]([NH:24][C:25]4[CH:26]=[C:27]([C:31]5[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=5)[CH:28]=[CH:29][CH:30]=4)=[N:21][N:20]=3)=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(C1C=CC(NC2OC(C(NC3C=CC([C@H]4CC[C@H](CC(OC)=O)CC4)=CC=3)=O)=NN=2)=CC=1)C>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[O:23][C:22]([NH:24][C:25]4[CH:26]=[C:27]([C:31]5[CH:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[CH:35][CH:36]=5)[CH:28]=[CH:29][CH:30]=4)=[N:21][N:20]=3)=[O:18])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2cccc(Nc3nnc(C(=O)Nc4ccc(N5CCN(C(C)=O)CC5)cc4)o3)c2)cc1
Agent: CCc1ccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)OC)CC4)cc3)o2)cc1
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3nnc(Nc4cccc(-c5ccc(C(=O)O)cc5)c4)o3)cc2)CC1

Procedure:
Following the procedure of Example 357 but using methyl 3′-{[5-({[4-(4-acetylpiperazin-1-yl)phenyl]amino}carbonyl)-1,3,4-oxadiazol-2-yl]amino}biphenyl-4-carboxylate as starting material in place of methyl (trans-4-{4-[({5-[(4-ethylphenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetate the title compound was obtained as a solid; 1H NMR δ 2.09 (s, 3H), 3.01-3.20 (m, 4H), 3.52-3.67 (m, 4H), 6.98 (d, 2H), 7.41 (d, 1H), 7.53 (t, 1H), 7.61-7.71 (m, 3H), 7.78 (d, 2H), 8.00 (s, 1H), 8.07 (d, 2H), 10.87 (s, 1H), 11.18 (s, 1H), 13.37 (s, 1H); MS m/e MH+ 527.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Se:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[C:6]1[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O>>[N+:1]([C:7]1[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[Se:5][C:6]=1[C:13]([OH:15])=[O:14])([O-:4])=[O:2]
Reactant: O=C(O)c1ccc(C(=O)O)[se]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(C(=O)O)[se]1
Reaction time: 2 h

Procedure:
Nitric acid (5.65 mL, 125.55 mmol, 70%) was added slowly to a mixture of selenophene-2,5-dicarboxylic acid (11 g, 50.2 mmol) in sulfuric acid (21.87 mL, 401.77 mmol) at 0-5° C. for 15 min. The mixture was allowed to rt with stifling slowly for 2 h, poured into ice cold water and stirred for 30 min. The solution was extracted with ethyl acetate (3×200 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as pale yellow color solid (10 g, 76%, it is a mixture of 2 compounds).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[N:17]=1.O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:17]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1CCl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1COc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.6 g or 4-t-butylphenol in 10 ml of DMF at 0° C., was added portionwise 0.13 g of 60% sodium hydride, and stirred at room temperature for 1 hour. 1.0 g of 5-chloromethyl-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4 triazole was added to the solution at 0° C., and stirred at room temperature overnight. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 1.3 g of 5-(4-t-butylphenoxymethyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole. m.p.84°-86° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CS(O[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Reactant: O=Cc1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1cccc(C=O)c1Br
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A mixture of 2-bromo-3-hydroxybenzaldehyde (5 g, 24.9 mmol), 3-(tert-butoxy carbonylamino)-propyl methanesulfonate (7.55 g, 30 mmol) and Cs2CO3 (24 g, 75 mmol) in DMF (60 mL) was stirred at 50° C. for 3 h and quenched with water (600 mL). The resulting mixture was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give the product (7.2 g, yield 81%). 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.53 (dd, J=7.8 Hz, 1.6 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12 (dd, J=8.2 Hz, 1.6 Hz, 1H), 5.16 (s, 1H), 4.15 (t, J=5.9 Hz, 2H), 3.42 (m, 2H), 2.10 (m, 2H), 1.44 (s, 9H); MS (ESI) m/z=358 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[CH:24][CH:25]=[C:7]2[C:6]=1[OH:26])=[O:4].[CH3:27][CH2:28][C@H:29]([NH2:33])[C:30]([OH:32])=[O:31].C[O-].[Na+]>>[OH:26][C:6]1[C:7]2[N:8]([CH:23]=[CH:24][CH:25]=2)[N:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[C:10](=[O:11])[C:5]=1[C:3]([NH:33][C@@H:29]([CH2:28][CH3:27])[C:30]([OH:32])=[O:31])=[O:4]
Reactant: CC[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: CC[C@H](NC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-2-aminobutyric acid and NaOMe. ESI (m/z): 438 (M+H)+.