Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Solvent: CO
Product: COC(=O)c1nc(CN2CCOCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1

Procedure:
A mixture of 8.8 g (0.018 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 3.5 ml (0.040 mole) of morpholine are stirred in 175 ml of methanol at 40° for 6 hours. The reaction mixture is thereupon concentrated in vacuo, water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed three times with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether, whereupon the reaction product is obtained in crystalline form. After filtration with suction and drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(morpholinomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 165°-170°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH2:10][C:11]1[CH:49]=[CH:48][CH:47]=[CH:46][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[C:28]([CH3:45])[CH:27]=2)[N:16]=1>C(Cl)Cl.C1CCCCC1>[CH3:45][C:28]1[CH:27]=[C:26]([NH:25][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:46]=[CH:47][CH:48]=[CH:49][C:11]=3[CH2:10][C:9]([NH2:8])=[O:50])[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=2)[CH:31]=[CH:30][C:29]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
TFA (1 mL) was added to a stirred solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A43) (0.16 g, 0.27 mmol) in DCM (4 mL) and the resulting solution was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then and the combined organic layers were washed with water (10 mL), brine (10 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a pale yellow solid. The solid was suspended in cyclohexane and the resulting suspension filtered to give the title compound 11 as a white solid (0.085 g, 64%); 1H NMR (400 MHz, d4-MeOH) δ 8.52 (s, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.23-7.15 (m, 4H), 3.67 (s, 2H), 3.23-3.11 (m, 4H), 3.10-3.01 (m, 2H), 2.91 (tt, J=11.7, 3.8 Hz, 1H), 2.80 (td, J=12.3, 2.8 Hz, 2H), 2.35 (s, 3H), 1.84-1.59 (m, 4H). LCMS-A: rt 4.962 min; m/z 498.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCCC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 48.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.2 g) and 5-amino-2-pyrrolidinobenzonitrile (0.8 g), the title compound (0.8 g) was obtained, melting point: 185° C.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH:4]1[C:9](=[O:10])[N:8](CC2C=CC(OC)=CC=2)[C:7]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:6]=2[O:5]1>C(#N)C.O>[CH2:3]1[CH2:1][CH:2]1[CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:6]=2[O:5]1
Reactant: COc1ccc(CN2C(=O)C(C3CC3)Oc3ccc([N+](=O)[O-])cc32)cc1
Solvent: O
Solvent: CC#N
Product: O=C1Nc2cc([N+](=O)[O-])ccc2OC1C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To solution of 400 mg 2-(2-cyclopropyl)-6-nitro-3-oxo-4-(p-methoxybenzyl)-benz[1,4]oxazine in acetonitrile/water (50 mL) was added 2.5 eq of ceric ammonium nitrate. The reaction mixture was stirred at ambient temperature for 18 hour, filtered, concentrated and the resulting residue partitioned between bicarbonate solution and EtOAc. The aqueous phase was extracted with EtOAc and the combined organics washed with water, brine and then dried over MgSO4. The solvent was removed in vacuo and the crude material purified by column chromatography (hexanes/EtOAc) to yield 250 mg of the desired product 2-(2-cyclopropyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine. MS (m/e): 341 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:24][OH:25])[CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:2]=1
Reactant: NO
Reactant: O=C(CCC1CCOCC1)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ON=C(CCC1CCOCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(3-pyridyl)-3-(4-oxanyl)propan-1-one (3.00 g, 13.7 mmol) was added saturated aqueous Na2CO3 (25 mL) and hydroxylamine hydrochloride (5.71 g, 82.2 mmol) in small portions. Solid K2CO3 was added to make the solution basic (pH>10). The reaction mixture was stirred overnight at ambient temperature and extracted with chloroform (4×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation. The resulting colorless viscous liquid (3.00 g, 93.8%) solidified upon standing at ambient temperature.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[N:20]1([CH2:26]Cl)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[N:12]([CH2:26][N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: ClCN1CCNCC1
Reactant: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21
Product: CCn1ncc2c1ncc1c(=O)n3nccc3n(CN3CCNCC3)c12

Procedure:
By reacting the product of Example 1 with piperazinomethyl chloride instead of 1-bromo-3-methylbutane as in Example 2, 3-ethyl-3,11-dihydro-11-(1-piperazino)methyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Na+].[PH2](O)=O.Cl.Cl.[NH:16]([C:20]1[S:21][CH:22]=[C:23]([C:25]([C:27]2[N:28]=[C:29](N)[NH:30][CH:31]=2)=[O:26])[N:24]=1)[C:17]([NH2:19])=[NH:18].C(=O)([O-])[O-].[Na+].[Na+].C>O.CO>[NH:16]([C:20]1[S:21][CH:22]=[C:23]([C:25]([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)=[O:26])[N:24]=1)[C:17]([NH2:19])=[NH:18]
Reactant: N=C(N)Nc1nc(C(=O)c2c[nH]c(N)n2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: N=C(N)Nc1nc(C(=O)c2c[nH]cn2)cs1
Reaction time: 0.17 h
Yield: 4.5 %

Procedure:
A mixture of 42 ml of concentrated sulfuric acid and 21 ml of water was cooled to -10° and 1.56 g (22.7 mmol) of sodium nitrate was added. Afrer stirring at -5° for ten minutes, 8.1 ml (78 mmol) of cold 50% hypophosphorous acid was added and stirring was continued for another 10 minutes at -5°. A solution of 2.5 g (8.4 mmol) of 2-guanidino-4-(2-amino- 4-imidazoyl)thiazole dihydrochloride in 100 ml of water was added dropwise over 0.5 hour. The reaction was stirred at 50° for 2 hours, then at room temperature for 16 hours. The reaction mixture was diluted with 500 ml of water, made basic with solid sodium carbonate and extracted three times with 150 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and evaporated leaving a solid. This solid was taken up into boiling methanol, decolorized with charcoal, and concentrated to a small volume. The resulting solid was collected and dried, thereby affording 90 mg (5%) of 2-guanidino-4-(4-imidazoyl)thiazole identical to the material of Example 31 by thin layer chromatography and high resolution mass spectrometry.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:2]1([C:1]2[O:18][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1cccs1
Yield: 77.5 %

Procedure:
1.5 g of ethyl 3-benzoylamino-3-(2-thienylcarbonyl)propionate, 10 ml of dimethylformamide and 0.5 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.1 g of ethyl 2-[2-phenyl-5-(2-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:13][N:14]2[CH:23]=[C:22]([S:24][CH2:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:39]4[CH:44]=[C:43]([C:45](=[O:50])[NH:46][CH:47]5[CH2:49][CH2:48]5)[CH:42]=[C:41]([F:51])[C:40]=4[CH3:52])[CH:20]=3)[C:15]2=[O:53])[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.C(O)C>Cl.O1CCOCC1>[CH:47]1([NH:46][C:45](=[O:50])[C:43]2[CH:44]=[C:39]([C:19]3[CH:20]=[C:21]4[C:16](=[CH:17][CH:18]=3)[C:15](=[O:53])[N:14]([CH2:13][C:10]3([CH2:9][OH:8])[CH2:12][CH2:11]3)[CH:23]=[C:22]4[S:24][CH2:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[C:40]([CH3:52])=[C:41]([F:51])[CH:42]=2)[CH2:49][CH2:48]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CC3)cc(SC[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO)CC3)cc(SC[C@@H]3CCCNC3)c2c1
Yield: 79.6 %

Procedure:
A solution of tert-Butyl (3R)-3-{[(2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopropyl]methyl}-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]methyl}piperidine-1-carboxylate (Example 63e, 110 mg) in 4N HCl in dioxane (1 mL) and ethanol (3 mL) was stirred for 20 h before being concentrated in vacuo. The residue was dissolved in methanol (2 mL) and loaded onto a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1N methanolic ammonia (50 mL) and evaporated in vacuo to afford the title product (63 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:27]C)[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:23][C:22]([NH2:24])=[CH:21][CH:20]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:25][CH3:26])C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>O1CCCC1>[CH3:27][N:3]([CH3:1])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:23][C:22]([NH:24][C:37]([NH:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:38])=[CH:21][CH:20]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:25][CH3:26]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCN(CC)CCCOc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2c(Sc3ccc(NC(=O)Nc4ccc(F)cc4)s3)ccnc2cc1OCCCN(C)C
Yield: 6.7 %

Procedure:
5-({7-[3-(Diethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine (190 mg), parafluorophenyl isocyanate (69 mg) and tetrahydrofuran (30 ml) were stirred together at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=10:1) using NH type silica gel. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for solidification to obtain 16 mg of a yellowish-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[CH:7]=1.C([O-])=O.[NH4+]>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:14])=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[CH:7]=1
Reactant: Cc1cn(-c2cc(F)ccc2[N+](=O)[O-])cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: Cc1cn(-c2cc(F)ccc2N)cn1
Yield: 104.9 %

Procedure:
Reaction of intermediate 1A (20.2 g, 91.4 mmol), 10% Pd/C (5.0 g, 4.57 mmol), and ammonium formate (34.7 g, 502.7 mmol) provided the product 2A as an off-white solid (18.34 g, 99% yield). EIMS 192.0 [M+H]+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[C:47]([F:48])[C:39]1=2)#[N:27].CO>C1COCC1.CO.O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:51])=[O:50])[CH:46]=[C:47]([F:48])[C:39]1=2)#[N:27]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)cc(F)c21
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)cc(F)c21
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.071 g, 0.322 mmol) was added THF (0.955 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.351 ml, 0.351 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was stirred for 1 hr (ice melt) providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture dried under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr the mixture was dried under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.074 g, 0.153 mmol, 52.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.39 (br. s., 2 H) 3.80-4.20 (m, 2 H) 6.87 (d, J=4.50 Hz, 1 H) 7.12 (dd, J=10.71, 2.01 Hz, 1 H) 7.20 (t, J=1.66 Hz, 1 H) 7.30 (d, J=4.69 Hz, 1 H) 7.41 (d, J=8.80 Hz, 1 H) 7.91-7.96 (m, 1 H) 8.35 (d, J=2.15 Hz, 1 H) 12.83 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[K+].[N+:17]([O-])([OH:19])=[O:18]>C(OCC)C>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)([O-])c1ccc(Br)c2ccccc12
Agent: [K+]
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2c(Br)ccc(S(=O)(=O)O)c12
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Potassium 4-bromo-naphthalene-1-sulfonate (1.38 g, 4.24 mmol) was added portionwise over 20 minutes to 90% nitric acid (2 mL), which was cooled in a methanol/ice bath to approximately -15° C. After 1.5 hours, the mixture was placed in a refrigerator for 20 hours. Diethyl ether (20 mL) was added and the precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 4:1 mixture of the 5- and 8-nitro isomers (1.25 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[C:25]([O:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH:24]=2)=[O:22])[CH3:19])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:24]=2)=[O:22])[CH3:19])=[O:17])[CH2:10][CH2:9]1
Reactant: CN(CC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 250 mg of the compound prepared in (a) in 2 ml of trifluoroacetic acid was stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, ether was added and deposited crystals were collected by filtration to give 168 mg of the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C1COCC1>[CH2:4]([O:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:11][CH2:10][C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH2:17][CH2:16]1)[CH2:1][CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](O)CC2)CC1
Solvent: C1CCOC1
Product: CCCCO[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCC)CC2)CC1
Reaction time: 2 h

Procedure:
0.5 g of 35% KH dispersion is added to a solution of 0.9 g of trans-4-[2-(trans-4-n-propylcyclohexyl)ethyl]-cyclohexanol in 250 ml of THF and stirring is carried out for two hours under reflux. Then 0.6 g of n-iodobutane is added and stirring is carried out for two hours at room temperature. Excess potassium hydride is destroyed with water. Extraction is carried out with methylene chloride, drying is carried with Na2SO4 and the solvent evaporated off. The residue left behind is worked up chromatographically. 1-(trans-4-n-butoxycyclohexyl)-2-(trans-4-n-propylcyclohexyl)ethane is obtained.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1>>[CH3:43][C:39]1([CH3:44])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]2[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]3[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=3)[CH:42]=[CH:41][C:40]1=2
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: CC1(C)CCC(C)(C)c2cc(/C(=C/c3ccc(CO)cc3)[Si](C)(C)C)ccc21

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether (Compound 2, 0.89 g, 2.0 mmol) and 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (0.60 g, 2.25 mmol) were coupled to give the title compound. 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene can be prepared in accordance with the procedure set forth in J. Med. Chem. 34:2930-41 (1994). The pentamethyl derivative thereof can be prepared in accordance with the same procedure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[OH-].C[Sn+](C)C>ClCCCl.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylate (0.080 g, 0.23 mmol) in DCE (8 mL) was added trimethyltin hydroxide (0.300 g, 1.66 mmol) and the resulting solution stirred at 80° C. overnight. A further portion of trimethyltin hydroxide (0.168 g, 0.93 mmol) was added and the solution stirred at 80° C. overnight. The reaction was diluted with DCM and washed with 1M aqueous HCl and brine. The organic phase was dried over MgSO4 and solvent removed in vacuo. The residue was purified by silica gel column chromatography using an 8% to 50% EtOAc in hexanes gradient followed by a 5% to 50% MeOH in DCM gradient to afford 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid (0.030 g, 0.095 mmol, 41% three steps). LCMS (1) Rt: 1.46 min; m/z (ES+) 317.
Reaction SMILES: C1([Li])C=CC=CC=1.[Br:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>CCOCC.O1CCCC1>[Br:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=1)=[O:20]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Brc1ccsc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(=O)c2sccc2Br)c1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A solution of phenyllithium (210 ml, 2.1M in cyclohexane) was added dropwise to a solution of 66 g of 3-bromothiophene in 400 ml of anhydrous ether at 5° C. The entire process was conducted under nitrogen. After the addition, the solution was stirred overnight under nitrogen. The resultant solution was then added dropwise to a solution of m-methoxybenzoyl chloride (90 g) in 600 ml of tetrahydrofuran at -70° C. over two hours and thereafter stirring was continued for two hours at the same temperature. The reaction was then quenched with water, the organics were extracted into ether, and the ether phase was washed with 10% sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. Upon evaporation of the solvent, an oily liquid was obtained which was chromatographed over alumina. Elution with hexane and thereafter with 10%, 20% and 50% ether/hexane gave 89.1 g of an oil which was vacuum distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:6]#N.[H-].[OH2:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH:6]=[O:18]
Reactant: O
Reactant: COc1cc(C#N)ccc1-c1ccccn1
Agent: [H-]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1-c1ccccn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3-methyoxy-4-pyridin-2-ylbenzonitrile (600 mg, 2.64 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. and was treated with diisobutylalumnium hydride (3.2 mL of 1M in CH2Cl2, 3.2 mmol). After stirring the reaction mixture at −78° C. for 2 h, the temperature was raised to −40° C. before quenching the reaction with a mixture of silica gel (6 g) and water (2 mL) and then warmed to rt. The reaction mixture was dried (K2CO3 and MgSO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:4 to 1:1) to afford 3-methoxy-4-pyridin-2-ylbenzaldehyde.