Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])[C@@H:3]([CH3:12])[O:4]CC1C=CC=CC=1.CCCCCC>CCOC(C)=O.[Pd]>[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:2]([C:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])[C@@H:3]([CH3:12])[OH:4]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCCC1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCCC1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Pd/C (3.3 g) was added to a stirring solution of Boc-Thr(Bzl)-OcHex (11 g, 30 mmol) in AcOEt (80 mL), and the reaction mixture was vigorously stirred under a hydrogen atmosphere for overnight. The catalyst was filtered off through Celite and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, at first with AcOE:hexane 1:4 and then the desired product was washed out by AcOE:hexane 1:1 to give pure Boc-Thr-OcHex (8.6 g, 28 mmol, 94%). 1H NMR (CDCl3 400 MHz) b 5.26 (br. d, 1H), 4.89-4.82 (m, 1H), 4.30-4.20 (m, 2H), 1.94 (d, J=5.6 Hz, 1H), 1.86-1.83 (m, 2H), 1.74-1.70 (m, 2H), 1.57-1.48 (m, 3H), 1.46 (s, 9H), 1.44-1.30 (m, 3H), 1.25 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])(C(=O)C)[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=[C:33](C=CC=1)[C:34]([O:36]O)=[O:35]>C(Cl)Cl.C(OCC)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([O:36][C:34](=[O:35])[CH3:33])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:7][CH:8]=1
Reactant: CC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
To 2.0 g (4.7 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4-acetyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 13a) in 10 ml of methylene chloride was added 2 g (9.8 mmole) of 85% 3-chloroperoxybenzoic acid (MCPBA). After standing for 72 hours at room temperature an additional 0.6 g of MCPBA was added and the reaction was let stand an additional 72 hours. The reaction mixture was diluted with diethyl ether, washed with dilute aqueous sodium bisulfite, dilute aqueous sodium bicarbonate, and brine. The resulting solution was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and crystallized from diethyl ether and hexanes to yield the title compound, a white solid, mp 92°-96° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)=[N:5][C:6]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C1COCC1>[CH2:9]([C:6]1[N:5]=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:3]([CH2:2][NH:1][S:59]([CH3:58])(=[O:61])=[O:60])=[CH:8][N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ncc(CN)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ncc(CNS(C)(=O)=O)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
5-Aminomethyl-2-butyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine, the intermediate from Example 32, is dissolved in THF containing triethylamine and treated with one equivalent of methanesulfonyl chloride. After the reaction is complete according to TLC analysis, the reaction mixture is washed with dilute aqueous sodium bicarbonate solution, dried and concentrated in vacuo to give 2-butyl-5-[methanesulfonamidomethyl]-4-{N-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine. The triphenylmethyl group is removed, as described in Example 1D, to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)(=[O:12])[CH3:11]>Cl.C(O)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]([C:10](=[O:12])/[CH:11]=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14]1
Reactant: CC(=O)c1ccsc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(O)cc1)c1ccsc1

Procedure:
10 g 4-hydroxybenzaldehyde and 10.4 g 3-acetyl thiophene were dissolved in 40 ml of a solution of 4% hydrochloric acid in acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.0 g, 9 mmol), (prepared as described for the starting material in Example 4), ethyl bromoacetate (1.11 ml, 10 mmol) and potassium carbonate (2.84 g, 20.6 mmol) in NMP (60 ml) was heated at 90° C. for 3 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and concentrated by evaporation. Hexane was added, the mixture was cooled and the precipitated solid was collected by filtration to give 4-(4-chloro-2-fluoroanilino)-7-(ethoxycarbonylmethoxy)-6-methoxyquinazoline (1.75 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:9]([CH3:17])([C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH3:10])C(OC)=O.[Li+].[Cl-].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:9]([CH3:10])([C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH3:17]
Reactant: COC(=O)C(C(=O)OC)C(C)(C)c1ccc(C)o1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CC(C)(C)c1ccc(C)o1
Temperature: 170 °C
Yield: 78 %

Procedure:
Step C To a solution of 2-[1-methyl-1-(5-methyl-furan-2-yl)-ethyl]-malonic acid dimethyl ester (2.5 g, 9.8 mmol) in DMSO (30 mL) was added LiCl (1 g, 23.7 mmol) and H2O (0.17 mL, 9.8 mmol). The reaction mixture was heated at 170° C. for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, 1:20) to give 3-methyl-3-(5-methyl-furan-2-yl)-butyric acid methyl ester as a colorless oil (1.5 g, 78%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([F:27])[CH:21]=1)=[O:19]>C(OCC)(=O)C.O>[F:27][C:22]1[CH:21]=[C:20]([C:18](=[O:19])[CH3:17])[CH:25]=[CH:24][C:23]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2ccnc2)c(F)c1

Procedure:
Imidazole (543 mg) and potassium carbonate (1.80 g) were added to a DMF (15 mL) solution of 3,4-difluoroacetophenone (1.0 mL). After agitating reaction solution at 80° C. for 4 hours, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=5:1→ethyl acetate), and 1.40 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)(O)=[O:2].C(C[N:16]1C(S)=NN=N1)(O)=O>>[C:1]([CH2:4][CH2:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)(=[O:2])[NH2:16]
Reactant: O=C(O)CCn1nnnc1S
Reactant: O=C(O)Cn1nnnc1S
Product: NC(=O)CCn1nnnc1S

Procedure:
When an equivalent amount of 1-(2-carboxyethyl)tetrazole-5-thiol was substituted in the procedure of Example 5 for 1-carboxymethyltetrazole-5-thiol, 1-(2-carbamoylethyl)tetrazole-5-thiol was obtained, m.p. 181°-182° (dec.).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1nc(-c2ccc(C(F)(F)F)nc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1

Procedure:
The title compound was prepared from 4-(6-trifluoromethyl-pyridin-3-yl)-6-trifluoromethyl-1H-pyrimidin-2-one (6.87 g, 0.022 mol) and phosphoroxychloride (35 ml) according to the general procedure I. Obtained as a light brown solid (7.18 g, 99%). MS (ISP) 329.2 [(M+H)+]; mp 87° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:15]([CH2:19]Br)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C([O-])=[O:33].[NH4+].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:15]([CH2:19][OH:33])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reactant: O=C([O-])C(F)(F)F
Agent: [I-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C1=C(CO)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of tert-butyl 7-phenylacetamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide (76.1 g; 0.158 mol) in N,N-dimethylformamide (350 ml), ammonium trifluoroacetate (41.3 g; 0.316 mol) and sodium iodide (23.6 g; 0.158 mol) were added, followed by stirring at room temperature. The reaction mixture was added with ammonium trifluoroacetate (10.3 g; 0.079 mol) upon an elapsed time of 4 hours and 35 minutes from the initiation of the stirring and then with sodium iodide (11.8 g, 0.079 mol) upon an elapsed time of 8 hours and 5 minutes after the initiation of the stirring. Stirring was continued at room temperature for 24 hours and 25 minutes in total. The reaction mixture was poured into a mixture of ethyl acetate, and water and the ethyl acetate layer was collected. The water layer was extracted twice with ethyl acetate. Ethyl acetate layers were combined together, successively washed with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby tert-butyl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate-1-oxide was obtained (yield: 63.5 g; 96.1%). NMR (CDCl3, δ): 1.58(9 H,s), 3.00(1 H,br.s), 3.17,3.94(2 H,ABq, J=18.7 Hz), 3.62(2 H,s), 4.13,4.47 (2 H,ABq,J=13.2 Hz), 4.42(1 H,d,J=4.8 Hz), 6.02(1 H,dd,J=4.8 Hz,9.7 Hz), 6.90(1 H,d,J=9.7 Hz), 7.24-7.30(5 H,m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]O)[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:30])[N:16]([CH3:31])[C:15]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:12][C:4]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:30])[N:16]([CH3:31])[C:15]1=[O:32]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Yield: 87.9 %

Procedure:
In 20 ml of anhydrous tetrahydrofuran were suspended 0.68 g of 2-methoxy-4-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3 -hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a) and 1.1 g of triphenylphosphine, and 0.71 ml of diethyl azodicarboxylate was added to the resultant suspension. Afterward, the mixture was treated in the same manner as in Reference Example 4, followed by recrystallizing from methanol to obtain 1.35 g of oily 1,3-dimethyl-6-[4-(3-[2-methoxy-4-nitrophenyloxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound w).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.CC(C)=O.[CH3:12][O:13][C:14]([C:16]1[C:25]([CH3:26])=[C:24]([O:27]C(=O)C)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:31])[CH:22]=2)[CH:17]=1)=[O:15]>CO>[CH3:12][O:13][C:14]([C:16]1[C:25]([CH3:26])=[C:24]([OH:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:31])[CH:22]=2)[CH:17]=1)=[O:15]
Reactant: COC(=O)c1cc2ccc(F)cc2c(OC(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
A heterogeneous mixture of potassium carbonate (46 g, 0.33 mol), water (260 mL), and acetone (260 mL) was added in three portions to a 0° C. solution of 4-acetoxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (18.4 g, 0.066 mol) in methanol (1 L). The resulting mixture was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The remaining oily suspension was diluted with ethyl acetate and washed with 1 N aqueous HCl. The organic phase was dried (MgSO4), filtered, and concentrated to yield 9.64 g (62%) of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester as a yellowish tan solid. HRMS (ES−) cald. for C13H11FO3 [(M−H)−] 233.0619, obsd. 233.0619.
Reaction SMILES: [OH-].[Na+].S(=O)(=O)(O)O.[NH2:8][CH2:9][C:10]#[N:11].[CH3:12][O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>O.C(OCC)(=O)C>[CH3:12][O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:11][CH2:10][C:9]#[N:8])=[O:20])=[CH:17][CH:16]=1
Reactant: COCc1ccc(C(=O)Cl)cc1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1ccc(C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (18.868, 0.47M) was dissolved in water (150 ml) and added to a stirred mixture of aminoacetonitrile bisulphate (24.23 g, 0.157M) and 4-methoxymethyl benzoyl chloride (29.9 g, 0.157M) in ethyl acetate (150 ml). The reaction was stirred for 21/2 hours at room temperature, the ethyl acetate layer was separated off and the aqueous layer re-extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulphate and evaporated to give a white solid. This was recrystallised from chloroform 80:100 petrol to give white plates, (24.5 gm), mpt 107°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13](=[O:18])[C:14](=[CH2:17])[CH2:15][CH3:16])[O:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>>[O:18]=[C:13]1[C:12]2[C:11](=[CH:10][C:4]([O:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=2[Br:1])[CH2:17][CH:14]1[CH2:15][CH3:16]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: CCC1Cc2cc(OCC(=O)O)cc(Br)c2C1=O

Procedure:
By following substantially the procedure described in Example 1, Step A, and using as the reactants [3-bromo-4-(2-methylenebutyryl)phenoxy]acetic acid and concentrated sulfuric acid, there is obtained crude product which after recrystallization from acetic acid yields substantially pure (1-oxo-2-ethyl-7-bromo-5-indanyloxy)acetic acid, m.p. 146°-148° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]>>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4](=[O:12])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: O=c1nc(Cl)c2ccccc2o1
Agent: Cl
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nc(=O)oc3ccccc23)CC1

Procedure:
The title compound was prepared starting from 4-chloro-benzo[e][1,3]oxazin-2-one (prepared from benzo [e][1,3]oxazin-2,4-dione and PCl5 in refluxing toluene) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81. MS, m/z 438=M+1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=3)[CH:3]=2)(=[O:10])=[O:9])=[C:13]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:14]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(Br)c2)c(S(N)(=O)=O)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2cccc(-c3cccc(OC(F)(F)F)c3)c2)c(S(N)(=O)=O)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
Pd(OAc)2 (44 mg, 0.19 mmol) was added to a solution of 2-(3-bromobenzenesulfonylamino)-5-methyl-benzensulfonamide (Example 150a) (0.40 g, 0.98 mmol), 3-(trifluoromethoxy)benzeneboronic acid (0.61 g, 2.96 mmol), tricyclohexyl phosphine (82 mg, 0.29 mmol) and potassium phosphate (0.42 g, 1.19 mmol) in toluene (10 mL). A few drops of water were added and the reaction mixture was stirred at 110° C. overnight. The reaction mixture was then diluted with 1N HCl and the product was extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:3) to afford the title compound (140 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].Cl[CH2:19][C:20](=O)[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:20]([CH3:21])=[CH:19][O:15][C:10]=2[CH2:9]1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (mp157-158° C.; 1.11 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (15 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.35 g).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]>CCO.[Pd]>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Reaction time: 20 h
Yield: 88.6 %

Procedure:
To a solution of 4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[6-(4-nitrophenoxy)-3-pyridyl]ethyl}pyridine (600 mg, 1.13 mmol) from Example 6, Step 5 in 20 mL EtOH, was added 120 mg of Pd/C 10% and the resulting mixture was stirred 20 h under H2 atmosphere. The reaction was filtered on celite, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% EtOH/Ethyl acetate) to afford the amine as an oil (500 mg, 88%).
Reaction SMILES: [CH3:1][C:2]([NH:17]C(=O)C(F)(F)F)([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:16][C:2]([NH2:17])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc(-c2ccc(CC(C)(C)NC(=O)C(F)(F)F)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(CC(C)(C)N)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
In a round-bottomed flask, N-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethyl}-2,2,2-trifluoroacetamide (˜362 mg, 1.06 mmol) was suspended in 7.5 ml of 2:1 (v:v) methanol/tetrahydrofuran, and 5M sodium hydroxide (3.2 ml, 15 equiv.) was added dropwise. The solution turned from colorless to golden brown, and was then allowed to stir at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove volatiles, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqeuous layer was removed and was washed twice more with ethyl acetate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product (242 mg, 93% yield for both steps), which was used directly without further purification. LRMS ([M+1]+)=247.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid (936 mg, crude) in DMF (10 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (442 mg), HOBt (588 mg), and EDCI (676 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl at solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (945 mg) as pale yellow form.