Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:22])=[CH:8][C:3]=1[C:4](OC)=[O:5].C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.CCOC(C)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:22])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: CCc1ccc(C(=O)c2cc(Br)c(C(=O)OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-bromo-5-chloro-4-(4-ethylbenzoyl)benzoate (7.64 g, 20 mmol) in 2,2,2-trifluoroacetic acid (38 mL) was added triethylsilane (5.88 mL, 40 mmol) under argon. After it was stirred for 10 min at room temperature, trifluoromethanesulfonic acid (0.1 mL) was added. The reaction temperature was raised from 26° C. to reflux. After stirring for 2 h, TLC (PE:EtOAc=6:1, Rf=0.7) showed the reaction was complete. The reaction mixture was evaporated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed 2× with H2O, 2× with NaHCO3, and 2× with brine, and then dried over anhydrous Na2SO4 Concentration under reduced pressure provided the title compound as a white solid. Yield: 7.2 g (100%). 1H-NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 7.07 (s, 1H), 4.05 (s, 2H), 3.92 (s, 3H), 2.63 (q, J=7.8 Hz, 2H), 1.24 (t, J=7.8 Hz, 3H).
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[C:8]([Si:12]([CH3:28])([CH3:27])[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=1)([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[S:3](=[O:4])(=[O:5])([O:23][C:17]1[C:16]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:14]([O:13][Si:12]([C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:27])[CH3:28])=[CH:19][C:18]=1[CH:20]([CH3:22])[CH3:21])[NH2:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
N-Chlorosulfonyl isocyanate (3.43 mL, 39.4 mmol) was added to a warm solution of 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropylphenol (11.59 g, 37.6 mmol) in 400 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and stirred overnight. The reaction was concentrated in vacuo, and the residue was quenched with ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an orange oil. Chromatography on silica gel gave 6.06 g of 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropylphenyl sulfamate as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]3[C:22](=[O:25])[NH:23][N:24]=[C:14]3[C:13]3[CH:26]=[CH:27][CH:28]=[N:29][C:12]2=3)=[O:10])[CH2:4][CH2:3]1.[H-].[Na+].[N:32]1([CH2:37][CH2:38][CH2:39]Cl)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[N:32]1([CH2:37][CH2:38][CH2:39][N:23]2[C:22](=[O:25])[N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:11]([C:9](=[O:10])[CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[C:12]4[N:29]=[CH:28][CH:27]=[CH:26][C:13]=4[C:14]3=[N:24]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CN1CCN(CC(=O)N2c3ccccc3-n3c(n[nH]c3=O)-c3cccnc32)CC1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CN1CCN(CC(=O)N2c3ccccc3-n3c(nn(CCCN4CCCC4)c3=O)-c3cccnc32)CC1
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (3-pyrrolidinopropyl)chloride in xylene is added. The mixture is kept at 95°-100°C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-(3-pyrrolidinopropyl)-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>CC(N(C)C)=O>[N:21]1([C:2]2[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16), in DMA was treated with a large excess of azetidine (˜30 eq). The resultant solution was warmed to 100° C. and stirred at that temperature for 18 h. The reaction solution was cooled to rt, poured into 1N NaOH solution and then extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate gradient (MeOH—CH3CN (1:7)/CH2Cl2) to give 2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine, I-23, as a white solid (88% yield).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:15][P:16]([CH:21]([NH2:23])[CH3:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>>[CH2:18]([O:17][P:16]([CH:21]([NH:23][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:22])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: CCOP(=O)(OCC)C(C)N
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: CCOP(=O)(OCC)C(C)Nc1ccc(C#N)cc1[N+](=O)[O-]
Yield: 77.4 %

Procedure:
2.77 g (15.24 mmol) of 4-chloro-3-nitrobenzonitrile is stirred with 10.5 g (38 mmol) of 1-aminoethanephosphonic acid diethyl ester for 16 hours at 30° C. The reaction mixture is then chromatographed on silica gel with methylene chloride:ethanol=95:5 as eluant. 3.86 g (80% of theory) of 1-[N-(2-nitro-4-cyanophenyl)amino]ethanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5]CO)[CH3:3].[F:8][CH:9]([F:34])[N:10]1[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[C:13](=[O:23])[C:12]([C:24]([O:26][CH2:27]CN(CC)CC)=[O:25])=[CH:11]1>>[F:8][CH:9]([F:34])[N:10]1[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[C:13](=[O:23])[C:12]([C:24]([O:26][CH2:27][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:25])=[CH:11]1
Reactant: CN(C)CCCO
Reactant: CCN(CC)CCOC(=O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3
Product: CN(C)CCCOC(=O)c1cn(C(F)F)c2cc3c(cc2c1=O)OCO3

Procedure:
The product can be obtained by substituting 3-(N,N-dimethylamino)-n-propanol for the 2-(N,N-dimethylamino)ethanol of Example 3.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:17]>>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyrimidyl) piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as a white amorphous solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4]C=1.C([C@@H]1COC(=O)[N:39]1C(=O)[C@H](CS(N1CCN(C2N=CC(C3C=NC=CC=3)=CN=2)CC1)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH3:30][CH:28]([CH3:29])[C@@H:24]([CH2:23][S:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:39][CH:2]=[CH:7][CH:6]=3)=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[C:25]([OH:27])=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)O
Yield: 61 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-{3-methyl-2-(R)-[4-(5-pyridin-3-ylpyrimidin-2-yl)piperazine-1-sulfonylmethyl]butyryl}oxazolidin-2-one (0.353 g), to give the title compound as a white solid (0.157 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:21][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: N#Cc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CCN
Product: CCNc1nc(Cl)nc2c1COCC2c1ccc(C#N)cc1

Procedure:
4-(2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile (Preparation AA) was reacted as described in Preparation Xa with ethanamine to give 4-(2-chloro-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile (Preparation AAa). LC-MS (M+H)+=315.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:36]([N:49]1[CH2:52][CH:51](OS(C)(=O)=O)[CH2:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH:36]([N:49]1[CH2:52][CH:51]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7]2)[CH2:50]1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Temperature: 100 °C
Yield: 38.1 %

Procedure:
In a microwave vial 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (300 mg, 0.73 mmol) was dissolved in DMF (6 ml) and cesium carbonate (713 mg, 2.19 mmol) and methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (347 mg, 1.09 mmol) were added. The vial was sealed and heated in a microwave reactor at 100° C. 3 h. The reaction was cooled, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 30% EtOAc/hexanes to provide 176 mg (38%) of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as an orange foam.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([CH:18]1[CH2:19][C:14]([N:13]([CH3:27])[CH3:12])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:16][C:17]1=[O:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF (30 ml) in argon and mixed with a solution of butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at −30° C. (bath temperature. The reaction mixture was cooled to −78° C. After this temperature was reached, 4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in dry THF (10 ml), was added in drops within 15 min. The batch was left for 30 min at −78° C. Benzyl bromide (3.6 ml, 30 mmol), dissolved in dry THF (20 ml), was then added within 10 min. The reaction mixture was stirred for a further 15 min at 78° C. (?), then the cooling removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous solution extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated NH4Cl solution (2×40 ml). The organic phases were then mixed with 1N HCl (50 ml) and thoroughly shaken out. The acid aqueous phase was separated, the organic phase washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 70 ml of 2N NaOH. An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over MgSO4 and then concentrated to low volume. One of the possible diastereoisomers was isolated from the residue (2.27 g) by chromatographic purification [silica gel 60 (50 g); ethyl acetate (1000 ml)].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br>S1(CCCC1)(=O)=O>[O:31]1[CH:29]([CH3:27])[CH:30]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)[nH]c(=O)c2c1
Temperature: 25 °C

Procedure:
4.5 gm (16.7 mmols) of 2-(4-hydroxy-phenyl)-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 50 ml of sulfolane, and the solution was mixed, while stirring, with 2.55 gm (16.7 mmols+10%) of potassium carbonate. After a clear solution was formed, 4.5 ml of epibromohydrin were added, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was poured into ice water, and the resulting crystalline precipitate was suction-filtered off, washed well with water and dried.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1CCCC=C[CH:22]=1>>[C:1]1([CH:7]([N:9]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]3[CH:12]=[CH:11][CH:10]2[CH2:20][CH2:21][CH2:22]3)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=CCCCC=C1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](C2)N1[C@@H](C)c1ccccc1
Product: CCOC(=O)C1C2C=CC(CCC2)N1C(C)c1ccccc1

Procedure:
In the reaction (a) of Example 1, 1,3-cycloheptadiene is used in place of cyclopentadiene, to give ethyl 6-(1-phenylethyl)-6-azabicyclo[3.2.2]non-8-ene-7-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][O:33][C:34]1[CH:38]=[C:37]([CH2:39]O)[N:36]([CH3:41])[N:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([O:23][CH2:39][C:37]4[N:36]([CH3:41])[N:35]=[C:34]([O:33][CH3:32])[CH:38]=4)=[CH:20][C:21]=3[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COc1cc(CO)n(C)n1
Reactant: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCc4cc(OC)nn4C)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.50 g, 1.2 mmol), (3-methoxy-1-methyl-1H-pyrazol-5-yl)methanol (0.17 g, 1.2 mmol) and tributylphosphine (0.59 mL, 2.4 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.60 g, 2.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, diisopropyl ether was added to the residue, and the resultant insoluble material was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give the title compound (0.44 g, yield 68%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][C:23](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCSc1nnc(N)s1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCSc1nn2c(=O)cc(-c3ccccc3)nc2s1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Three point seven (3.7) grams of 2-amino-5-hexylthio-1,3,4-thiadiazole, 3.4 g of ethyl benzoylacetate and 5 g of polyphosphoric acid were mixed and stirred at 130°-140° C. for 30 minutes. After cooling, chloroform and water were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 5.5 g of 2-hexylthio-7-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 99%. This substance was recrystallized from ethanol and the purified compound showed a m.p. of 90°-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[C:5]([NH:7][C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([C:16]([F:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[CH2:26][CH3:27])=[O:6].C(N(CC)CC)C.[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1>ClCCl>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH:1][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=2[N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[C:5]([NH:7][C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([C:16]([F:25])([C:17]([F:19])([F:20])[F:18])[C:21]([F:22])([F:23])[F:24])=[CH:10][C:9]=2[CH2:26][CH3:27])=[O:6])=[O:49])=[CH:46][CH:45]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1NC(=O)c1ccc(-n2cncn2)c(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 3-amino-N-[2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)phenyl]-4-(1,2,4-triazol-1-yl)benzamide (75 mg, 0.15 mmol) (Example I4) in dichloromethane (3 ml) was added triethylamine (63 μl, 0.45 mmol) and 4-fluorobenzoyl chloride (21.3 μl, 0.18 mmol). The reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of saturated aqueous sodium hydrogen carbonate (5 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×5 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was purification by column chromatography on silica gel (eluent: hexane/ethyl acetate 1:4) to give Compound No. D2 of Table D (76 mg, 82% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[N:34]1[O:35][C:36]([C:43](O)=[O:44])=[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43]([C:36]3[O:35][N:34]=[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=34)=[O:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)c1onc2ccccc12
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4onc5ccccc45)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.8 g, 5.7 mmol) in DMF (20 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 g, 6.8 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.9 g, 6.8 mmol) and benzo[c]isoxazole-3-carboxylic acid (1.0 g, 6.3 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.5 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford benzo[c]isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a yellow solid (1.93 g, 78%): mp, 253-255° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.6 min (96%); 1H NMR (DMSO-d6): δ 2.08-2.13 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.94 (m, 1H), 5.02 (d, J=6.0 Hz, 2H), 5.19 (dd, J=6, 12 Hz, 1H), 7.27-7.97 (m, 5H), 9.90 (t, J=6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 21.98, 30.93, 40.33, 48.89, 115.15, 118.27, 120.74, 122.07, 127.24, 131.54, 131.96, 133.20, 134.88, 138.13, 156.43, 156.52, 156.97, 160.91, 166.93, 167.49, 169.82, 172.75. Anal Calcd for C22H16N4O6+0.2H2O: C, 60.61; H, 3.79; N, 12.85. Found: C, 60.38; H, 3.50; N, 12.80.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.ClC1C=C(N2[C:24]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27](Cl)[CH:26]=3)=[CH:23][C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=N2)C=CC=1F>>[F:31][C:29]1[CH:30]=[C:25]([C:24]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[N:11]=[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(NN)c1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2cccc(OC)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 8A and 3-methoxyphenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 30.4 g (62% of theory) of the title compound are obtained.