Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.P(Cl)(Cl)Cl.[N+:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[OH:23])([O-:13])=[O:12]>C1C=CC=CC=1>[OH:23][C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)=[O:18]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: Nc1nnn[nH]1
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1O
Yield: 22.9 %

Procedure:
Anhydrous 5-aminotetrazole (15 g) and phosphorus trichloride (6 ml) were added to a suspension of 3-nitrosalicylic acid (16 g) in dry benzene (250 ml). The mixture was stirred and heated at reflux for 20 hours. The mixture was then cooled and diluted with petroleum ether (b.p. 60°-80° C.; 250 ml) and the resulting solid was filtered off. The solid was treated with dilute hydrochloric acid (200 ml; 2N) and the mixture was stirred for 30 minutes, and the solid was then filtered off and washed with ethanol and dissolved in aqueous ammonia solution (2N). This solution was treated with decolourizing charcoal and filtered and the filtrate was acidified by treatment with concentrated hydrochloric acid to give 2-hydroxy-3-nitro-N-(tetrazol-5-yl)benzamide (5.0 g), m.p. 236°-238° C. (with decomposition).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][N:15]1[CH2:14][CH2:13][C@@H:10]2[N:11]3[CH2:1][CH2:2][O:3][C:4]4[CH:5]=[CH:6][CH:7]=[C:8]([C:12]3=4)[C@@H:9]2[CH2:16]1
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3

Procedure:
The title compound was prepared by the method of Example 355 Step B as a yellow oil (172 mg, 57%) from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-[2,3,4-hi]pyrido[4,3-b]indole (165 mg, 0.76 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (329 mg, 1.5 mmol). The title compound was spectroscopically identical to Example 529.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:38])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[CH:35]([CH3:37])[CH3:36])[NH2:31]>>[CH3:38][N:24]([CH3:23])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:22])[CH:32]=[CH:33][C:34]=1[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)c1ccc(N)cc1OCCN(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(C(C)C)c(OCCN(C)C)c4)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP0533268A1) and 3-(2-dimethylaminoethoxy)-4-isopropylaniline (D56) using a similar procedure to Example 20 (89%). The freebase was converted to the oxalate salt mp 219°-223° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:10]1[N:11]=[C:12]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)[CH:13]=[CH:14][CH:15]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cccc(Br)n2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
cis-2,6-Dimethylmorpholine (0.535 g, 4.64 mmol) was added to a suspension of 2,6-dibromopyridine (1 g, 4.22 mmol) and potassium carbonate (1.750 g, 12.66 mmol) in anhydrous acetonitrile (35 mL). After addition, the reaction mixture was stirred at 120° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (185 mg, 1.61 mmol) was added to the reaction mixture which was then stirred at 120° C. overnight. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (705 mg, 2.340 mmol, 55.4% yield). LC/MS [M+H]+=271/273.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH:5]=[CH2:6].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>>[CH2:4]([C:5]([CH3:6])=[C:9]1[CH:8]=[CH:12][CH:11]=[CH:10]1)[CH2:3][CH:2]=[CH2:1]
Reactant: C1=CCC=C1
Reactant: C=CCCC(C)=O
Product: C=CCCC(C)=C1C=CC=C1

Procedure:
A process according to claim 5 wherein 5-hexene-2-one is reacted with cyclopentadiene to yield 6-(3-butenyl)-6-methylfulvene which is then reacted with fluorenyllithium and then subjected to hydrolysis to yield 5-cyclopentadienyl-5-(9-fluorenyl )-1-hexene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:18](OC)(OC)([O:22][CH3:23])[CH2:19][CH2:20][CH3:21]>>[CH3:23][O:22][C:18](=[N:17][S:14]([C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1)(=[O:16])=[O:15])[CH2:19][CH2:20][CH3:21]
Reactant: COc1ccc(-c2nsc(S(N)(=O)=O)n2)cc1
Reactant: CCCC(OC)(OC)OC
Product: CCCC(=NS(=O)(=O)c1nc(-c2ccc(OC)cc2)ns1)OC
Yield: 93.6 %

Procedure:
A mixture of 1.5 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide and 4.1 g of trimethyl orthobutyrate was warmed at reflux for 0.5 hour. The mixture was cooled and triturated with hexane (3×) to give 1.84 g of solid. Recrystallization from cyclohexane/benzene (6:1) gave 1.63 g of fluffy solid. This was combined with 0.7 g sample from another identical small scale reaction. This combined material (2.33 g) had m.p. 159°-161°.
Reaction SMILES: Cl[O-].[Na+].[OH:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[Na+].[I-:17].[OH-].[Na+].[Na+].[Cl-]>CO.O.C(Cl)Cl>[OH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([I:17])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: [I-]
Reactant: COC(=O)c1cccc(C)c1O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(I)cc(C(=O)O)c1O
Temperature: -5 °C
Reaction time: 120 h

Procedure:
14.9 mL (24.1 mmol) sodium hypochlorite solution (10 percent by weight in water) is added dropwise to a solution of 4.0 g (24.1 mmol) methyl 2-hydroxy-3-methyl-benzoate, 3.6 g (24.1 mmol) NaI, 0.96 g (24.1 mmol) NaOH in 100 mL MeOH at −5° C. over 40 min. The reaction is stirred for 30 min at −5° C. and 5 days at RT. The solvent is eliminated i.vac. and the residue is taken up in 80 mL water and 50 mL DCM. After the organic phase has been saturated with NaCl it is extracted twice with DCM. The combined organic extracts are filtered and the solvent is eliminated i.vac. The product is further reacted without any more purification.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:34]([CH2:35][CH3:36])[CH2:32][CH3:33]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(C)c(Oc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI/CI): predicted mass C25H27N5O3, 445.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=3)=[CH:42][CH:41]=2)[N:34]=1.[CH2:61](O)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])=[CH:37][CH:36]=[C:35]([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=3)=[CH:44][CH:45]=2)[N:34]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(O)c(F)n3)cc2)cc1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCCCC)c(F)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.02 ml (6.45 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 1.70 g (6.45 mmol) of triphenylphosphine in 100 ml of tetrahydrofuran and the mixture is stirred at room temperature for 30 minutes. 1.70 g (4.30 mmol) of 2-fluoro-3-hydroxy-6-[4-(4-octyloxyphenyl)phenyl]pyridine and 0.56 g (4.30 mm 1-octanol are then added. After a reaction time of 18 hours, the precipitated product is filtered off and purified by chromatography (silica gel, dichloromethane) and by recrystallization from acetonitrile, giving 1.13 g of 2-fluoro-3-octyloxy-6-[4-(4-octyloxyphenyl)phenyl]pyridine. ##STR26##
Reaction SMILES: [N:1]1([NH:6][C:7]2[C:8]([CH3:19])=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[CH3:18])[CH2:5][CH2:4][N:3]=[CH:2]1.CC[O:22]CC.[ClH:25]>CO>[OH2:22].[ClH:25].[ClH:25].[N:1]1([NH:6][C:7]2[C:8]([CH3:19])=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[CH3:18])[CH2:5][CH2:4][N:3]=[CH:2]1
Reactant: CCOCC
Agent: Cc1cc(NN2C=NCC2)c(C)c2c(C)ccnc12
Agent: Cl
Solvent: CO
Product: O
Reaction time: 72 h

Procedure:
6-(2-Imidazolinylamino)-4,5,8-trimethylquinoline (0.406 g) is dissolved in a solution of concentrated hydrochloric acid (0.813 mL) in methanol (4 mL). To this solution is added ether (7 mL). The solution is allowed to stand at room temperature for 3 days, and the resulting crystals are filtered and washed with ether to provide 6-(2-imidazolinylamino)-4,5,8-trimethylquinoline dihydrochloride monohydrate.
Reaction SMILES: [NH2:1][C@:2]1([CH2:14][OH:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.N1C=CC=CC=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCOCC1.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:22](=[O:23])[O:15][CH2:14]3)[CH2:3]2)=[CH:8][CH:9]=1
Reactant: N[C@]1(CO)CC[C@H](c2ccc(Br)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)CO1
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a mixture of ((1R,3S)-1-amino-3-(4-bromophenyl)cyclopentyl)methanol (11 g, 40.7 mmol) and pyridine (I-3A, 3.29 mL, 40.7 mmol) in dioxane (300 mL) was added 1,1′-carbonyldiimidazole (19.81 g, 122 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M HCl, brine and saturated NaHCO3. The mixture was back extracted several times. The organic layer was dried with MgSO4, filtered and concentrated to afford 10.5 g of desired product as an off-white solid. HPLC retention time=0.87 min (Condition G). LC/MS M+1=297.9; 1H NMR (400 MHz, chloroform-d) δ 7.45 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.42 (br. s., 1H), 4.41-4.21 (m, 2H), 3.17-2.91 (m, 1H), 2.34 (dd, J=13.3, 7.4 Hz, 1H), 2.23-2.11 (m, 2H), 2.01-1.90 (m, 2H), 1.88-1.74 (m, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[C:23]([O:28][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.CO.O>[CH3:35][S:32]([CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[N:18]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a suspension of 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-yl-amino}-cyclohexanecarboxylic acid ethyl ester (35.4 g, 70 mmol) in THF (180 mL) and MeOH (200 mL) was added a solution of LiOH-H2O (14.69 g) in H2O (150 mL). The resulting mixture was briefly heated in a steam bath and stirred at RT with a mechanical stirrer for 1 h to provide a light yellow solution. The reaction mixture was concentrated in vacuo and diluted with cold H2O and the pH was adjusted to 6 with 10% HCl. The resulting solid was filtered, washed several times with cold H2O and finally with EtOH at 0° C. The resulting solid product was then dried in vacuo to provide 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclo-hexanecarboxylic acid (32.2 g, 97.4%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][OH:14])=[O:8])=[CH:9][CH:10]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.8 %

Procedure:
To a solution of 4-bromobenzoic acid (892 mg, 4.44 mmol) in THF (9.9 mL) was added (S)-2-amino-2-phenylethanol (609 mg, 4.44 mmol), DIEA (1.9 mL, 11.1 mmol), PyBroP (2.5 g, 5.32 mmol), and HOBT (815 mg, 5.32 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. After dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography (gradient EtOAc in DCM) yielding (S)-4-bromo-N-(2-hydroxy-1-phenylethyl)benzamide (850 mg, 60%). LCMS (m/z): 338.1 (MH+), 0.61 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([NH:18]C(=O)OC(C)(C)C)=[CH:17][C:11]=3[CH:10]=2)[O:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([CH3:26])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:11]=3[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2sc(B3OC(C)(C)C(C)(C)O3)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(c2cc3cc(N)ccc3s2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)carbamate (7.51 g, 20 mmol, 1 eq) in anhydrous dichloromethane (40 mL under nitrogen atmosphere at 0° C. was added dropwise trifluoroacetic acid (15.4 mL, 10 eq) and the reaction was stirred at 0° C. for 30 minutes followed by at room temperature for about two hours. The reaction was then slowly poured into an ice-cold saturated aqueous sodium bicarbonate solution with stirring and the white solid that appeared during the process was filtered, washed with water, to give a first batch of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine in the amount of 2.792 g. The pH of the filtrate was adjusted to 8 by addition of solid sodium bicarbonate with stirring and then extracted using chloroform (3×). All organic layers were combined, dried with anhydrous sodium sulfate, and concentrated down to give brown oil. After the oil was placed in vacuo for two hours, it was treated with EtOAc-Hex (1:9) and the mixture was stirred at room temperature for 30 minutes. A second batch of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine was isolated as a pale pink solid in the amount of 1.883 g upon filtration. The total amount of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine is 4.675 g with a yield of 85%.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:20]=[CH:21][CH2:22][CH3:23]>CCOCC>[CH:21]([C:13]1[CH:14]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[C:10]([CH:1]([CH2:2][CH3:3])[CH3:8])[C:11]=1[NH2:12])([CH2:22][CH3:23])[CH3:20]
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: C=CCC
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Solvent: CCOCC
Product: CCC(C)c1cc(Cc2ccccc2)cc(C(C)CC)c1N

Procedure:
81 g of 4-benzylaniline, 1.2 g of aluminium powder, 3.6 g of anhydrous aluminium chloride and 100 g of but-1-ene are heated for 24 hours at +260° C. in an autoclave. After cooling, the reaction mass is poured into ice-cold dilute sodium hydroxide solution and taken up in ether. The ether phase is separated off, dried over sodium sulfate and subjected to fractional distillation; b.p. 130°-134° C./0.03 torr. Chromatographic purification on silica gel using hexane/ethyl acetate as eluant affords the title compound of formula ##STR12## in the form of a colourless oil; refractive index nD24 : 1.5579.
Reaction SMILES: [N:1]([CH:4]1[CH:7]([CH2:8][C:9](=[O:23])[C:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N+]=[N-])[NH:6][C:5]1=[O:24])=[N+:2]=[N-:3]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[N:1]([CH:4]1[C:5](=[O:24])[N:6]2[CH:7]1[CH2:8][C:9](=[O:23])[CH:10]2[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C(=O)NC1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Temperature: 80 °C

Procedure:
A suspension of rhodium acetate (2 mg) and 3-azido-4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)azetidin-2-one (1 mmol) in anhydrous benzene (20 ml) is deoxygenated by bubbling nitrogen through it for 15 mins. The suspension is then stirred with heating in an oil bath at 80° C. for 30 min. After cooling to room temperature, the mixture is filtered and the filtrate is evaporated under vacuum to provide benzyl 6-azido-1-azabicyclo[3.2.0]-heptan-3,7-dione-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O:38]=[C:39]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:40][C:41](O)=[O:42].C(Cl)CCl>CN(C=O)C>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:39](=[O:38])[NH:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(O)CC(=O)Nc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 46 (333 mg, 0.631 mmol) in DMF (8 mL) at RT was added 3-oxo-3-(phenylamino)propanoic acid (226 mg, 2 eq, 1.262 mmol) and EDC (242 mg, 2 eq, 1.262 mmol), and the reaction mixture was stirred at RT for 24 hours. It was then concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47a (357 mg, 82% yield) as a white solid. MS (m/z): 689.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Product: NS(=O)(=O)Oc1cccc(Cl)c1
Yield: 7.6 %

Procedure:
By the procedure of Example 34,96 g (0.75 mole) of 3-chlorophenol and 67.5 ml (0.75 mole) of chlorosulfonyl isocyanate gave 122.9 g of solid product. A 25 g portion was recrystallized from 100 ml of toluene to give 11.8 g of white solid, mp 82°-83° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 43.4 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 16; 100 mg) was reacted with 1-acetylpiperazine (73.0 mg) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (50.9 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([S:12](Cl)(=O)=O)[CH:3]=1.CN(C)C(=O)C.Cl[Si](Cl)(C)C>ClCCCl.[Zn]>[SH:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cc1cc(S(=O)(=O)Cl)cc2oc(=O)[nH]c12
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: Cc1cc(S)cc2oc(=O)[nH]c12
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere a solution of 1.40 g (5.60 mmol) 4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-sulphonic acid chloride and 1.60 g (16.8 mmol) N,N-dimethylacetamide in 1,2-dichloroethane was slowly added dropwise to 1.30 g (19.9 mmol) zinc and 2.40 mL (19.5 mmol) dichlorodimethylsilane in 20 mL of 1,2-dichloroethane. The reaction mixture was stirred for 2 h at 75° C. After cooling the mixture was filtered and the filtrate was evaporated down. The residue remaining was combined with MeOH, the precipitate formed was filtered and the filtrate was evaporated down. The residue was further reacted as the crude product.