Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C=NC1CCCC1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)NC2CCCC2)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 31% yield. LCMS for C30H35ClN7O2 (M+H)+: m/z=560.2.
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[C:9]3[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1)CCC.C(OCC)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:39]5[CH:44]=[N:43][CH:42]=[CH:41][N:40]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc2c(cc1-c1cnccn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3

Procedure:
A solution of 60 mg of 7k and 125 mg of 2-tributylstannyl pyrazine and 13 mg of Pd(PPh3)4 was heated in 2 ml of degassed toluene, under N2 atmosphere for 16 hr. The reaction mixture was concentrated and the crude material was chromatographed over silica gel, using a gradient of toluene/ethyl acetate as eluent. The material thus isolated was treated with diethyl ether, to provide 13 mg of crystalline 7m; Mp 267-268° C.; MS-ESI: [M+1] 529.3.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[NH:9][C:8](=[O:16])[CH:7]([NH:17]C(=O)C)[CH2:6]2>C(O)C>[ClH:1].[CH2:8]([OH:16])[CH3:7].[ClH:1].[NH2:17][CH:7]1[CH2:6][C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:3]([Br:2])[CH:4]=2)[NH:9][C:8]1=[O:16]
Reactant: CC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Agent: Cl
Solvent: CCO
Product: NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O

Procedure:
Aqueous hydrochloric acid-ethanol solution was prepared (from commercial aqueous concentrated hydrochloric acid (3 L) and ethanol (6 L)), and N-(6-bromo-8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (known compound: Chem. Abst., 4150 (1947)) (604 g) was added to the solution, followed by heating for 14 hours under stirring and reflux. The reaction mixture was cooled on an ice bath, and the precipitates were recovered through filtration. The thus-obtained solid was washed with ethanol and dried, whereby the title compound (571 g) was yielded as a powdery compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:39]1([CH2:38][CH2:37][NH:36][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)[CH:28]=2)(=[O:35])=[O:34])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCN1CCOCC1)c1cccc(Br)c1
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-Bromo-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide (example B.20)(454 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow amorphous solid (60 mg, 10%). MS (ISP) 624.2 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:30])[CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:31](OC(=O)C)(=O)[CH3:32].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:31][C:32]1[O:1][C:2]2[C:3]([C:9](=[O:30])[CH:10]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8]
Reactant: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c2cccc(C)c2o1
Temperature: 25 °C

Procedure:
27.5 g (67 mmol) of 1-(2-hydroxy-3-methylphenyl)-2-(triphenylphosphoranylidene)ethanone in 200 ml of absolute toluene are heated to reflux. 13.7 g (134 mmol) of acetic anhydride and 11.1 g (141 mmol) of pyridine are slowly added dropwise to this solution. The reaction mixture is then heated under reflux for 6 h. After cooling to room temperature, the solution is washed with saturated sodium carbonate solution and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate 7:3→4:6). 7.5 g (64% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[N:23]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)c1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(S(C)(=O)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.13 g, 0.44 mmol) and 2-bromo-6-(methylsulfonyl)pyridine (0.10 g, 0.44 mmol) as the starting materials.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:4].N.[C:21]1([Mg][Cl:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:28].[CH3:4][N:3]([CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:12])[CH3:2]
Reactant: Cc1ccccc1C(C1CCCCC1=O)N(C)C
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(C1CCCCC1(O)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
The base was freed from 3.0g (10.6 mmole) of the hydrochloride of 2-(dimethylamino-o-tolylmethyl) cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.50 g (10.2 mmole) of this base were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 6.1 ml (12.2 mmole) of phenylmagnesium chloride (2 M solution in tetrahydro-furan), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.12 g of crude base (94.5% of theory) were obtained, from which 1.97 g of 2-(dimethylamino-o-tolylmethyl)-1-phenylcyclohexanol, hydrochloride (53.7% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 137° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:7][CH:6]=[C:5]([C:8](OC)=[O:9])[CH:4]=1.CO.[BH4-].[Na+]>C1COCC1>[F:12][C:2]([F:1])([F:13])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1
Reactant: COC(=O)c1csc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of methyl 5-(trifluoromethyl)thiophene-3-carboxylate (523 mg) in THF (1 ml)-MeOH (1 ml) was added NaBH4 (2.2 g) at room temperature, and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was quenched with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (449 mg) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[S:54][C:50]=2[C:49]([CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)=[CH:48][CH:47]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O1CCOCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:55][C:53]1[S:54][C:50]2[C:49]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[C:51]=2[N:52]=1)=[O:7]
Reactant: COc1ccc(C2CCCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a stirred solution of 0.99 g (4.92 mmol) 2-bromo-isonicotinic acid in 40 ml THF were added 2.16 g (5.67 mmol) HATU and 0.97 ml (5.67 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 1 h. A solution of 1.00 g (3.78 mmol) 4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-ylamine in 20 ml dioxane and 4 ml DMF was then added and stirring continued at room temperature for 48 h. The reaction mixture was then poured into aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were washed with 1 M hydrochloric acid, then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (acetone/hexane 1/4) followed by trituration in ether afforded 500 mg (29%) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 450 (M{81Br}+H+, 100), 448 (M{79Br}+H+, 80).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.O.[Li+].[OH-].Cl>C1COCC1.CCOC(C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[C:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2cnc3ccc(C=C=Cc4ccccc4)cc3c2=O)cc1
Yield: 29.6 %

Procedure:
0.105 g (0.257 mmol) of the compound of Example 9 is dissolved in 25 ml of 90% THF: 10% water. 10 equivalents of LiOH are added. The reaction is refluxed for 3 hours, 200 ml of EtOAc are added, acidified by concentrated HCl and the solution is washed with 2×100 ml of water and 1×100 ml of brine. Organic layer dried over MgSO4, and concentrated. The residue is purified on a silica gel column with 95% EtOAc, 5% MeOH to yield 30 mg of the product as a light yellow powder.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([CH:9]2[CH2:10][CH2:11][CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]2[CH2:6][CH:1]=[CH:2][CH2:3][N:8]2[CH:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:11][CH2:12][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(C2CCCC(c3ccccc3)N2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=CCN1C(c2ccccc2)CCCC1c1ccccc1)CN1C(c2ccccc2)CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 2,6-diphenylpiperidine [3.0 g, 12.6 mmol; prepared by the method of V. Baliah et al., Indian J. Chem., 16B, 1965 (1978)] and 1,4-but-2-enediol diacetate (1.1 g, 6.3 mmol) in tetrahydrofuran (20 ml, THF) is treated with tetrakis(triphenylphosphine)palladium (0) (0.65 g, 0.6 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to a solid that is redissolved in THF (100 ml) and treated with 20% aqueous sodium hydroxide (25 ml). The mixture is stirred for one hour, concentrated, and extracted with diethyl ether. The ether extracts are dried and concentrated giving an orange solid which is purified by crystallization from methanol to yield 2.02 g (61%) of the title compound as a white solid melting at 197°-200° C.
Reaction SMILES: F[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[CH:7]3[CH3:17])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH3:17][CH:7]1[N:6]2[C:11]([CH2:12][O:13][C:14]3[C:5]2=[CH:4][C:3]([N+:18]([O-:20])=[O:19])=[C:2]([O:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=3)=[N:10][NH:9][C:8]1=[O:16]
Reactant: CC1C(=O)NN=C2COc3cc(F)c([N+](=O)[O-])cc3N21
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1C(=O)NN=C2COc3cc(Oc4ccccc4)c([N+](=O)[O-])cc3N21
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.7 %

Procedure:
A mixture of 7-fluoro-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.30 g, 1.07 mmol), K2CO3 (0.296 g, 2.14 mmol) and phenol (0.151 g, 1.61 mmol) in acetone (10 mL) was stirred at ambient temperature for 48 h and then heated to reflux for 3 h. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between EtOAc (30 mL) and water (10 mL). The organic portion was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silical gel (eluting with 15% EtOAc in petroleum ether) to give 4-methyl-6-nitro-7-phenoxy-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.090 g, 24%) as an orange solid. LC/MS (Table 1, Method 2) Rt=1.117 min; MS m/z: 355 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccc(Cl)c(Cl)c3)nc2n1
Temperature: 125 °C
Yield: 58.8 %

Procedure:
The procedure is similar to that described in Example 24, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 3,4-dichlorophenol (65.2 g) and potassium hydroxide pellets (85% pure; 13.2 g), heating to 125° C. for 22 hours. On recrystallization in acetonitrile (1500 cc) of the crude product obtained, 2-amino-7-(3,4-dichlorophenoxy)-1,8-naphthyridine (18 g), m.p. 206° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH:10](O)[CH2:11][N+:12]([O-:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]=[CH:11][N+:12]([O-:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(O)C[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC=C[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To (3-Hydroxy-1,1-dimethyl-4-nitro-butyl)-carbamic acid tert-butyl ester (2.00 g, 7.6 mmol) and triethylamine (2.73 g, 27.0 mmol) in 50 mL CH2Cl2 at −10° C. was added dropwise over 5 min. methanesulfonyl chloride. The mixture was warmed to rt for 1 h, and then was diluted with water and extracted with CH2Cl2 (3×30 mL). The extracts were washed sequentially with 1% HCl, water and brine and were dried over MgSO4 and concentrated. Silica gel chromatography (10:1 hexane/EtOAc) gave 1.07 g (60%) of a colorless oil: 1H NMR (300 MHz, CD3OD) d 7.1–7.4 (comp, 2H), 2.72 (d, 2H, J 7.5 Hz), 1.46(s, 9H), 1.31 (s, 6H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH3:14])[CH3:10].[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH2:9]([O:11][C:12](=[O:23])[C:13]([CH3:14])([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH:36]([C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:39][CH:38]=1)[OH:37])[CH3:10]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)Oc1ccccc1C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(C)(Oc1ccccc1C)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
A solution of LDA (34.9 mL, 52.4 mmol, 1.5M in cyclohexane) in anhydrous THF (60 mL) was cooled to −78° C. in a dry ice/acetone bath and added to a solution of 2-o-Tolyloxy-propionic acid ethyl ester in anhydrous THF (60 mL) also cooled to −78° C. under an atmosphere of nitrogen. After five minutes, 4-benzyloxybenzaldehyde (5.56 g, 26.2 mmol) was added in one portion. After stirring for one minute, the reaction mixture was quenched with acetic acid (5 mL, 87.4 mmol, d=1.049) and a saturated solution of aqueous NH4Cl (50 mL). The biphasic mixture was allowed to warm to room temperature and diluted with diethyl ether (1 L). The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (13% ethyl acetate in hexanes) to provide a mixture of diastereomers of the titled compound (6.36 g, 54%). 1H NMR (400 MHz, CDCl3): • 7.44-7.32 (m, 6H), 7.16-6.82 (m, 5H), 69.74-6.66 (m, 2H), 5.16 (d, 1H, J=3.52 Hz), 5.07 (s, 2H), 4.26-4.15 (m, 2H), 2.28 (s, 3H), 1.43 (s, 3H), 1.22-1.17 (m, 3H). Rf=0.25 in 25% ethyl acetate in hexanes.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][S:35]([CH3:34])(=[O:37])=[O:36])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reaction time: 3 h

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (504 mg) in tetrahydrofuran (8 ml) are added dropwise methanesulfonyl chloride (0.13 ml) and triethylamine (0.23 ml) under ice cooling. After 3 hours, the mixture is evaporated to leave residue, which is dissolved in methylene chloride, washed with water, dried over magnesium sulfate, and evaporated. Purification of the residue by chromatography over silica gel containing 10% water (15 g) using a mixture of benzene and ethyl acetate (5:1) gives p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate (353 mg). Colorless foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1>[Si]([O-])([O-])([O-])[O-].[Ag+].[Ag+].[Ag+].[Ag+].C(OCC)(=O)C>[CH3:18][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:20]2([CH3:28])[C@H:8]([C@H:7]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[CH:4]([CH2:3][C:2](=[O:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:19])[CH3:17]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Ag+]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 5 h

Procedure:
388.6 Mg of 3-hydroxy-cholestane, 500 mg of silver silicate and 30 ml of ethyl acetate were added to the flask of Example II and the reaction mixture was refluxed for 10 hours. Another 50 mg of silver silicate were added thereto and reflux was continued for 5 hours. The mixture was then filtered and the filtrate was concentrated to dryness. The residue was dissolved in ether and the ether was distilled off under reduced pressure to obtain 383 mg of cholestane-3-one melting at 115°C, then 128°C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C(OC(C)C)(C)C>[CH2:16]([NH:18][C:19]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:20])[CH3:17]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: CCN=C=O
Solvent: CC(C)OC(C)C
Product: CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A solution of 6.5 g (0.03 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether was stirred under a blanket of nitrogen while 2.85 g (0.04 mole) of ethyl isocyanate was added dropwise. After stirring for 2 hr at ambient temperature, a solid began to precipitate, and after 4 hr, the solid was collected by filtration to yield 3.7 g of beige product, m.p. 94°-96° C. Rework of the filtrate gave only a trace of additional product. The product was recrystallized from isopropyl ether/hexane (treated with charcoal) to yield 2.61 g (30%) of product, m.p. 109°-110° C.