Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]([NH2:53])=[O:52])=[O:48].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:51]([NH2:53])=[O:52])=[O:48])=[O:20])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: NCCCCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCCCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
457 mg (0.81 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 384 mg (0.81 mmol) of the compound from example 21A, 141 μl (0.81 mmol) N,N-diisopropylethylamine and 307 mg (0.81 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified in two portions by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 255 mg (0.22 mmol, 28% of theory) of the desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][OH:6])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[C:47](O)=[CH:46][CH:45]=[CH:44][N:43]=1)([O-:41])=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][O:6][C:47]1[C:42]([N+:39]([O-:41])=[O:40])=[N:43][CH:44]=[CH:45][CH:46]=1)[CH3:2]
Reactant: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])c1ncccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CCOc1cccnc1[N+](=O)[O-])CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.7 %

Procedure:
To a solution of compound 3 (11.3 g, 43.1 mmol) in anhydrous tetrahydrofuran (400 mL) were added successively, under argon, triphenylphosphine (11.3 g, 43.1 mmol), 2-nitro-3-hydroxypyridine (6.02 g, 43.0 mmol) and dropwise diisopropyl azodicarboxylate (8.70 mL, 44.2 mmol). The mixture was stirred at room temperature for 60 h and the solvent was evaporated under vacuum. Unreacted 2-nitro-3-hydroxypyridine was removed by chromatography (Al2O3., AcOEt/cyclohexane, 9/1, v/v). The residue containing the desired product was dissolved in dichloromethane (200 mL) and pentane (600 mL) was added. The mixture was stirred at room temperature for 5 min and the precipitate was filtered and dried under vacuum to give compound 58 (12.7 g, 33.0 mmol) as a yellow solid. Yield 77%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.76; mp 124-126° C.; IR (KBr) ν 1274, 1397, 1536, 1702, 1767, 2830 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.96 (t, 3H, J=7.1 Hz), 2.63 (q, 2H, J=7.1 Hz), 2.81 (t, 2H, J=6.4 Hz), 2.94 (t, 2H, J=5.8 Hz), 3.76 (t, 2H, J=6.4 Hz), 4.10 (t, 2H, J=5.8 Hz), 7.50 (m, 2H), 7.60 (m, 2H), 7.75 (m, 2H), 8.05 (dd, 1H, J=2.5, 3.4 Hz); ESI-MS m/z 385.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:42][CH:43]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(OC)cc3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccc(C(=O)NCCOc3ccc(CC(Oc4ccc(C(C)C)cc4)C(=O)O)cc3)cc2)cc1
Yield: 81.5 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-(4′-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (580 mg), which is the product of Example 88, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (450 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][C:41]3=[N:42][O:43][N:44]=[C:40]3[CH:39]=2)O1>CN(C=O)C.O>[N:42]1[O:43][N:44]=[C:40]2[CH:39]=[C:38]([C:2]3[CH:3]=[C:4]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=3[O:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)[CH:46]=[CH:45][C:41]=12
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(Br)c1
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL) were added Cs2CO3 (1.4 g, 4.342 mmol), Pd(TPP)4 (286 mg, 2.480 mmol) and 5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (355 mg, 1.364 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of Celite™ was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (250 mg) as an off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>CN(C=O)C>[NH:32]1[C:1]([C:3]2[CH:4]=[C:5]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:6]=[CH:7][C:8]=2[NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([C:21]([F:24])([F:22])[F:23])[CH:12]=2)=[N:2][N:34]=[N:33]1
Reactant: N#Cc1cc(-c2ccccc2)ccc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccccc2)cc1-c1nnn[nH]1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 109.2 %

Procedure:
N-[3-cyano-biphenyl-4-yl]-3,5-bis-trifluoromethyl-benzamide (100 mg), sodium azide (40 mg) and triethylamine hydrochloride (103 mg) were stirred at 100° C. for 20 hours in DMF (3 ml). The reaction mixture was poured into a 5% KHSO4 solution (10 ml) and the solid was filtered off and dried to give N-[3-(1H-Tetrazol-5-yl)-biphenyl-4-yl]-3,5-bis-trifluoromethyl-benzamide as a white solid (120 mg). Mp.=156° C. (dec.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:11][CH2:10][C:9](=[O:12])[C:8]4[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=4[S:6]3(=[O:18])=[O:17])[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cn1ccc2c1C(=O)CCN(CCCCl)S2(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: Cn1ccc2c1C(=O)CCN(CCCN1CCC(C(=O)c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 74.2 %

Procedure:
A suspension of 116 mg (0.4 mmol) of Compound 18, 97 mg (0.4 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 5 ml of acetonitrile was refluxed for 17 hours. Post treatment was conducted as in Example 13, and the residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=3/97), whereby 137 mg of the title compound were obtained (yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][C:14](=O)[CH3:15])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:25])[CH3:9]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccnc2)c1-c1ccccc1

Procedure:
3-Aminopyridine (5 mmol, 0.5 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over silica, but still contained contaminants. This material was triturated in hexane, and the solids were separated by filtration. The solids were washed with benzene two times to yield the named product (m.p. 102° C.-103° C.).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH:12](OCC)[O:13]CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCOC(=O)c1ccccc1)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=CCCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a stirred solution of 5.0 grams (0.020 mole) of 3-ethoxy-4-oxahexyl benzoate in 100 ml of tetrahydrofuran was added 100 ml of aqueous 5% hydrochloric acid. The reaction mixture was stirred at ambient temperature for three hours, and then it was poured into 100 ml of water. The mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 1.9 grams of 3-oxopropyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Na].[C:14](=[O:16])=[O:15]>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C=O
Agent: [Na]
Solvent: Cc1ccccc1C
Product: Cc1cc(C(=O)O)c(O)c(C(C)(C)C)c1

Procedure:
One hundred and sixty four grams of 2-tertiarybutyl-4-methylphenol is dissolved in 500 ml. of xylene. 23 g. of dried metal sodium is added therein and dissolved. The resulting product is a suspension of white powder in xylene. The product is placed in a porcelain ball mill having a capacity of 1000 ml., and milled for about 3 hours. The product is placed in an autoclave having a capacity of 1000 ml. and carbon dioxide gas pressure of 20kg/cm2 is blown therein at about 150°C. to effect a reaction for about 5 hours. By same treatments thereof as in Examples 2 and 4, 3-tertiary butyl-5-methylsalicylic acid is produced.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.C(N(CC)CC)C.[O:29]=[C:30]1[CH2:34][CH2:33][C:32](=O)[CH:31]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]>C1C=CC=CC=1.O>[Br:20][C:32]1[CH2:33][CH2:34][C:30](=[O:29])[C:31]=1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: O=C(O)CCCCCCC1C(=O)CCC1=O
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CCCCCCC1=C(Br)CCC1=O
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 67 %

Procedure:
A dried triphenyl phosphine (288 mg) was dissolved in a dried benzene (10 ml), and then 1M bromine in benzene solution (1.1 ml) was added thereto while stirring at 0° C. over 3 minutes. The mixture was stirred for 10 minutes at room temperature, and then dried triethyl amine (0.15 ml) was added thereto at 0° C. Continuously, 7-(2,5-dioxocyclopentyl) heptanoic acid (113 mg) were added thereto. The mixture was stirred for 26 hours, and poured into the same volume of water. The aqueous solution was extracted with three 20 ml portions of ether. The ether layer was washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The reaction mixture was purified by thin layer chromatography to afford 7-(2-bromo-5-oxo-1-cyclopentenyl) heptanoic acid (yield 96.6 mg, 67%).
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:7][CH2:8][CH:9]=[O:10])[C:5]#[N:6])[CH3:3].P([O-])(O)(O)=[O:18].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>O.C(O)(C)(C)C>[C:5]([C:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH:2]([CH3:1])[CH3:3])[CH2:7][CH2:8][C:9]([OH:18])=[O:10])#[N:6]
Reactant: O=P([O-])(O)O
Reactant: CC(C)C(C#N)(CCC=O)c1ccccc1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)C(C#N)(CCC(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
2-(1-Methylethyl)-5-oxo-2-phenylpentane nitrile, 6.00 g 27.9 mmol, was dissolved in a mixed solvent of water 55 ml/t-butyl alcohol 200 ml, and sodium dihydrogen phosphate 4.35 g 27.9 mmol and 2-methyl-2-butene 14.8 ml 139 mmol were further added thereto. Sodium chlorite 10.0 g 111 mmol in limited amounts was added thereto and stirred for 2 hours. The reaction mixture was ice-cooled and acidified by 2N hydrochloric acid. Then, it was extracted with ether, washed with dilute hydrochloric acid, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 4.10 g 17.7 mmol, 63.4%, was obtained as a white solid.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:18]1([C:24]23[CH2:31][CH2:30][C:27]([CH2:32][OH:33])([CH2:28][CH2:29]2)[CH2:26][CH2:25]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:33][CH2:32][C:27]23[CH2:26][CH2:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)([CH2:29][CH2:28]2)[CH2:31][CH2:30]3)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OCC12CCC(c3ccccc3)(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4)(CC2)CC3)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Pyridine (4 mL), then a solution of toluene-4-sulfonyl chloride (7.4 g, 38.81 mmol) in dry DCM (30 mL), were added to a stirred solution of (4-phenylbicyclo[2.2.2]oct-1-yl)methanol (7.0 g, 32.36 mmol) in DCM (70 mL), maintaining 0-5° C. throughout. The reaction mixture was stirred at 0° C. overnight, refluxed for 2 h then cooled to 35° C. Further pyridine (2 mL) and a solution of toluene-4-sulfonyl chloride (3.9 g) in DCM (10 mL) were added and the mixture stirred at reflux for 2 h. As some starting material remained, a catalytic amount of 4-dimethylaminopyridine was added and the mixture stirred under reflux overnight. The mixture was cooled, diluted with DCM (200 mL) then washed with water (100 mL), hydrochloric acid (2M; 150 mL), water (50 mL), sat. aq. NaHCO3 (100 mL), water (50 mL) and brine (50 mL). After drying (MgSO4) the solution was concentrated to give crude product which was purified by silica column chromatography (silica 40-63 micron) eluting with hexane:ethyl acetate (19:1 to 4:1) to afford the title compound as a pale yellow solid (10.7 g, 89%).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[N:4]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[N:3]=1.[OH-].[Na+]>O>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[N:4]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])[N:3]=1
Reactant: CCOC(=O)C(C)n1nc(Br)c(Br)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(Br)c(Br)nn1C(C)C(=O)O
Yield: 85 %

Procedure:
A quantity (5.1 g., 0.015 mole) of the ethyl 3,4 -dibromo-α,5-dimethylpyrazole-1-acetate prepared in Part A, above, was added to a solution consisting of 0.8 g. (0.02 mole) sodium hydroxide in 100 ml. water and the resulting suspension was heated at the reflux temperature for 3 hrs. A clear, aqueous solution resulted. The aqueous solution was extracted with 50 ml. diethyl ether and the ether extract was discarded. The ether-extracted aqueous layer was then adjusted to pH 2 with 1.5 N hydrochloric acid and again extracted three times with 40 ml. portions of the ether. These ether extracts were combined, washed with three, 30 ml. portions of water, dried over anhydrous magnesium sulfate, and the ether was removed by evaporation under reduced pressure. There was thus obtained 4.0 g. (85% yield) of 3,4 -dibromo-α, 5-dimethylpyrazole-1-acetic acid having a melting point at 131° to 135.5° C. Recrystallization from a mixture of acetone and hexane gave the compound with a melting point at 138° C.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:16])(=[O:4])[CH3:3].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[Cl:31])=[O:23]>>[ClH:16].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[O:23])=[C:25]([Cl:31])[CH:26]=1)(=[O:4])[CH3:3]
Reactant: Nc1ccc(C(=O)c2cccs2)c(Cl)c1
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Agent: Cl
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(C(=O)c4cccs4)c(Cl)c3)c2c1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline hydrochloride was reacted with 4-amino-2-chlorophenyl 2-thienyl ketone to give 6-acetoxy-4-[3-chloro-4-(2-thienylcarbonyl)anilino]quinazoline hydrochloride salt in 77% yield, m.p. >250° C.;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:22].O>O1CCOCC1.[Cu-]=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]([CH3:20])[CH:10]=[N:9][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:22])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: Cn1cnc(-c2ccnc(Br)c2)c1-c1ccc(F)cc1
Agent: O=[Cu-]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccnc(N)c2)c1-c1ccc(F)cc1

Procedure:
The crude 2-Bromo-4-[5-(4-fluoro-phenyl)-1-methyl-1H-imidazol-4-yl]-pyridine (196 mg), 28% aqueous ammonium hydroxide solution (2.0 mL) and copper (I) oxide (84 mg, 0.59 mmol) are mixed in 1,4-dioxane (3.0 mL) in a microwave reaction tube. The mixture is heated at 150° C. for 25 min in a microwave reactor before water (30 mL) is added. The resulting mixture is extracted with EtOAc (3×25 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 72 mg of desired product.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[S:4]
Reactant: CN(C)C(=O)CCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)C(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 92.4 %

Procedure:
Thiosemicarbazide (2.75 g, 30.2 mmol) was added to a solution of 4-oxo-N,N-dimethyl-4-phenyl-butyramide (3.80 g, 18.5 mmol), prepared in the previous step, in 65 ml of methanol plus 5 ml of 1 N HCl plus 5 ml of water and the reaction stirred at room temperature for 28 hours. The solid present was collected by filtration to give 4.76 g of a white solid. The solid was triturated with water and then dried to give the title compound (4.53 g, 88%) as a white solid, mp 173-175° C.
Reaction SMILES: C([O:5][C:6](=[O:54])[C:7]([O:10]/[N:11]=[C:12](/[C:41]1[N:42]=[C:43]([NH:46]C(OC(C)(C)C)=O)[S:44][CH:45]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][CH2:32][NH:33]C(OC(C)(C)C)=O)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][C:29]1[N:28]=[N:27][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:54])=[O:5])/[C:41]3[N:42]=[C:43]([NH2:46])[S:44][CH:45]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:22])=[O:23])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)nn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CCN)nn1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
To a solution of (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (110 mg, 0.137 mmol) in DCM (1.4 mL) at 0° C. added TFA: DCM (1:1, 4.2 mL) followed by triethylsilane (65 μL, 0.411 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt it was concentrated in vacuo and triturated with MTBE:Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, acetonitrile: water solvent system with 0.1% formic acid modifier) to afford the title compound (5 mg, 7%); LCMS: m/z=543.9 (M−1); 1H NMR (400 MHz, MeOH-d4) δ 8.06 (s, 1H), 6.95 (s, 1H), 5.44 (d, J=5.8 Hz, 1H), 4.66 (q, J=6.0 Hz, 1H), 4.95-4.83 (m, 2H assumed; obscured by water), 3.29-3.24 (m, 2H), 3.07 (t, J=6.5 Hz, 2H), 1.54 (s, 3H), 1.52 (s, 3H).