Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:20])[NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:21]>CO.C1COCC1.O1CCOCC1>[ClH:21].[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:12]([CH:10]1[CH2:9][NH:8][CH2:11]1)=[O:20]
Reactant: COC(=O)CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCNC(=O)C1CNC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of 3-(2-Methoxycarbonyl-ethylcarbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.92 mmol) in MeOH (4 mL) and THF (2 mL) was treated with 4.0N HCl in 1,4-dioxane (4 mL) and stirred at 0° C. for 30 minutes and at room temperature for 5 hours. The solvent was removed in vacuo to yield the title compound as a gum (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:19][CH:18]4[CH2:20][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[F:28][C:29]([F:36])([F:35])[CH2:30][S:31]([NH:21][CH2:20][CH:18]1[CH2:19][C:17]1([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: O=S(=O)(CC(F)(F)F)NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 79.4 %

Procedure:
(2-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methanamine (71 mg, 0.15 mmol) was coupled with 2,2,2-trifluoroethanesulfonyl chloride (50 mg, 0.5 mmol) using General Coupling Method B to give 60 mg (86% yield) of 2,2,2-trifluoro-N-((2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methyl)ethanesulfonamide. MS found: (M+H)+=504.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:27]=3)=[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Fc1ccc(-c2nn3cccnc3c2Br)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3cccnc23)ccn1
Temperature: 150 °C
Yield: 16.9 %

Procedure:
3-Bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (150 mg, 0.51 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (148 mg, 0.56 mmol, 1.1 eq) are dissolved in 1.5 mL 1,4-dioxan. To this mixture, bis(tricyclohexylphosphine)palladium(II)-dichloride (57 mg, 0.07 mmol, 0.15 eq) and 0.83 mL sodium carbonate solution (2 molar) are added. The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 30 min at 150° C. in the microwave (Biotage). The reaction mixture is then poured in water and extracted with dichloromethane (3×20 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 1:1) as eluent and 0.03 g (17%) of N-{4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}acetamide are obtained as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:34]=[N:35][N:36]([CH:38]5[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]5)[CH:37]=4)=[CH:29][N:28]=3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:17]1.CCN(C(C)C)C(C)C.[O:53]1[CH2:56][C:55](=O)[CH2:54]1>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3[N:28]=[CH:29][C:30]([C:33]4[CH:34]=[N:35][N:36]([CH:38]5[CH2:43][CH2:42][N:41]([CH:55]6[CH2:56][O:53][CH2:54]6)[CH2:40][CH2:39]5)[CH:37]=4)=[CH:31][N:32]=3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:17]1
Reactant: O=C1COC1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(C6COC6)CC5)c4)cn3)c2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Sodium triacetoxyborohydride (0.13 g; 0.62 mmol; 2.0 eq.) was slowly added to a solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidine (example 1,200 mg; 0.31 mmol; 1.0 eq.), DIEA (53 μl; 0.31 mmol; 1.0 eq.) and 3-oxetanone (39 μl; 0.62 mmol; 2.0 eq.) in DCE (4 mL). The reaction mixture was then stirred at 50° C. for 3 h. It was then quenched by addition of water. Aqueous phase was basified to pH 12 and extracted with EtOAc (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige powder (100 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.59-8.50 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.18-8.11 (m, 1H), 7.96-7.89 (m, 1H), 7.77-7.66 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 4.23 (s, 1H), 3.90 (s, 3H), 3.51-3.40 (m, 1H), 2.87-2.73 (m, 2H), 2.17-1.90 (m, 6H). HPLC (Condition A): Rt 2.49 min (purity 97.2%). MS (ESI+): 442.5.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:7].[F:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:27][C@@H:28]1[CH2:31][CH2:30][NH:29]1>>[F:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:27][C@@H:28]1[CH2:31][CH2:30][N:29]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:7]
Reactant: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Reactant: Cc1ccc(C[C@@H]2CCN2)cc1F
Product: CCOC(=O)CC/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CC[C@H]1Cc1ccc(C)c(F)c1
Yield: 46 %

Procedure:
By using ethyl (4E)-5-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)pent-4-enoate which had been obtained in Example 13 (13a) and (2R)-2-(3-fluoro-4-methylbenzyl)azetidine which had been obtained in Example 14 (14e), the reaction was carried out in the same manner as the method described in Example 1 (1f) to give the title compound as a colorless oily substance (yield 46%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7](=[O:29])[C:8]2[C:9]3[N:18]([CH3:19])[C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[CH3:28])=[N:16][C:10]=3[CH:11]=[CH:12][C:13]=2[C:14]=1[CH3:15].[CH3:30][P:31]1(=[O:40])[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C.CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]2[N:18]([CH3:19])[C:9]3[C:8]4[C:7](=[O:29])[NH:6][C:5]([CH:4]=[CH:3][CH2:2][NH:1][C:37]([CH:34]5[CH2:35][CH2:36][P:31]([CH3:30])(=[O:40])[CH2:32][CH2:33]5)=[O:38])=[C:14]([CH3:15])[C:13]=4[CH:12]=[CH:11][C:10]=3[N:16]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCN)[nH]c(=O)c3c2n1C
Reactant: CP1(=O)CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCNC(=O)C4CCP(C)(=O)CC4)[nH]c(=O)c3c2n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.2 %

Procedure:
To scintillation vial with a magnetic stir-bar was added 7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (68 mg, 173 μmol), followed by dimethylformamide (DMF) (1.0 mL) and triethylamine (TEA) (0.25 mL). To a separate scintillation vial was added 1-methyl-1-oxo-1λ5-phosphinane-4-carboxylic acid (130 mg, 0.74 mmol, mixture of cis/trans isomers), HATU (300 mg, 0.79 mmol), and DMF (2.0 mL), followed by TEA (0.25 mL). The solution was sonicated until most of the solids were dissolved. A solution of the activated ester (1.0 mL, or roughly half) was transferred to the solution of amine and stirred for 2.5 hours at room temperature, after which time the starting material was completely consumed as determined by LC-MS. The reaction mixture was quenched by addition of water (0.5 mL), then acidified with TFA. The mixture was filtered (syringe membrane filter) and purified directly by reverse-phase HPLC to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (24.9 mg, 26%) as a mixture of cis/trans isomers. 1H NMR (400 MHz, d6-DMSO) δ 11.12 (s, 1H), 10.55 (s, 1H), 8.21-8.17 (m, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.55 (dd, J1=5.9 Hz, J2=9.0 Hz, 1H), 7.27 (td, J1=2.7 Hz, J2=8.6 Hz, 1H), 6.66 (d, J=15 Hz, 1H), 6.55-6.49 (m, 1H), 4.18 (s, 3H), 3.92 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.35-2.30 (m, 1H), 2.08-1.90 (m, 6H), 1.78-1.65 (m, 2H), 1.52-1.47 (m, 3H); ESMS m/z: found, 550 (M+1)+.
Reaction SMILES: C1(C)C=CC(S([O:10][C@@:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])([C@H:18]([N:20]2[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]2)[CH3:19])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)(=O)=O)=CC=1.[OH-].[Na+]>C(OCC)C>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C@:11]([OH:10])([C@H:18]([N:20]1[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]1)[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: C=C1CCN([C@H](C)[C@@](Cn2cncn2)(OS(=O)(=O)c2ccc(C)cc2)c2ccc(F)cc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C=C1CCN([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Yield: 74.3 %

Procedure:
To 18.3 g of the p-toluenesulfonate obtained above there were added 40 ml of ethyl ether and 35 ml of 1N aqueous solution of sodium hydroxide. The organic phase was taken out, and dried over 5 g of anhydrous magnesium sulfate and then the solvent was removed. There was added 40 ml of n-hexane to the residual liquid, and the precipitated crystal was separated by filtration, and dried to obtain 9.43 g of the desired (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol. 1H-NMR spectrum of this compound coincided with that of the compound in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)[CH:7]=1.[N:50]1(C(OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:80][C:81]([F:86])([F:85])[C:82]([OH:84])=[O:83]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:9]=2)[CH:7]=1.[C:82]([OH:84])([C:81]([F:86])([F:85])[F:80])=[O:83]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(CN4CCNCC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (21.94 mg, 0.118 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and a acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then the MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fiber filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.3 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give N-{[5-chloro-3′-(1-piperazinylmethyl)-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (21.9 mg, 49.6%) as a white solid. LC-MS m/z 749 M+; mp 119-122° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(CC)CC.[CH3:43][C:44]1([CH3:51])[O:49][CH2:48][C:47](=O)[CH2:46][O:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH:47]4[CH2:48][O:49][C:44]([CH3:51])([CH3:43])[O:45][CH2:46]4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: CC1(C)OCC(=O)CO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(N2CCC(c3ccc(NC(=O)c4nc(C#N)c[nH]4)c(C4=CCCCC4)c3)CC2)CO1
Reaction time: 3 h
Yield: 28.1 %

Procedure:
To a slurry of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (81 mg, 0.16 mmol, as prepared in Example 14, step (b)) in CH2Cl2 (3 mL) was added NEt3 (33μ, 0.24 mmol). The solution was then treated with 2,2-dimethyl-[1,3]dioxan-5-one (31 mg, 0.24 mmol) and the reaction was allowed to stir for 3 h. At this time NaBH(OAc)3 (51 mg, 0.24 mmol) was added in one portion, and the reaction was allowed to stir for an additional 4 h. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel preparative thin layer chromatography (10% MeOH—CHCl3) afforded 22 mg (28%) of the title compound as an off-white semi-solid. Mass spectrum (ESI, m/z): Calcd. for C28H35N5O3, 490.2 (M+H). found 490.6.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[SH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>C(#N)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([S:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: O=C(O)c1ccc(S)cc1
Solvent: CC#N
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Sc3ccc(C(=O)O)cc3)ncc21
Yield: 26.8 %

Procedure:
A solution of 2-Chloro-9-cyclopentyl-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.324 mmol) and 4-mercaptobenzoic acid (50 mg, 0.324 mmol) in acetonitrile (5 mL) was heated under reflux for 4 hours. Additional 4-mercaptobenzoic acid (50 mg, 0.324 mmol) was added and the reaction mixture was heated under reflux for 16 hours. After cooling, the crude reaction mixture was filtered through Celite and washed with acetonitrile. The crude product was purified by column chromatography (0%-10% MeOH: CH2Cl2) and triturated with MeOH to give the title compound (37 mg, 27% yield) as a white solid. NMR DMSO D6 1.03 (6H, s), 1.20-1.38 (6H, m), 1.42-1.53 (2H, m), 3.17 (3H, s), 3.27 (2H, s), 4.47 (1H, dt), 7.72 (2H, dd), 7.99 (2H, dd), 8.02 (1H, s); MS (ES+) 427, (ES−) 425.
Reaction SMILES: [CH:1]12[CH2:8][CH:4]([CH:5](O)[CH2:6]1)[CH:3]=[CH:2]2.[CH:9](O)=[O:10]>>[CH:1]12[CH2:8][CH:4]([CH:5]([CH2:9][OH:10])[CH2:6]1)[CH:3]=[CH:2]2
Reactant: OC1CC2C=CC1C2
Reactant: O=CO
Product: OCC1CC2C=CC1C2
Yield: 37 %

Procedure:
Norbornen-5-ol (25 g) was dissolved at 55° C. in 100 mL of formic acid (96%). Unless otherwise specified, all of the reagents specified in the examples herein are obtained from the Aldrich Chemical Co. After 2 hours gas chromatography (GC) indicated that all norbornen-5-ol was consumed. The reaction mixture was cooled down and 100 mL of ether was added. Then, the reaction mixture was extracted with 10×100 mL of water. The organic layer was separated, dried and ether was removed. The product was distilled at 75° C. (20 mm Hg). Yield: 17 g, 54% (95% pure by GC, no OH peak by IR). The same procedure afforded formyl ester of norbornen-5-methanol with 37% yield (b. p. 85° C., 20 mm Hg, 96% pure by GC).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].I[CH3:27]>O1CCCC1.C(OCC)C>[CH3:27][O:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCC(OC)c1coc([Si](C)(C)C)c1

Procedure:
A mixture of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (318.5 mg, 0.9 mmol), sodium hydride (60% dispersion in oil; 150 mg, 3.8 mmol) and iodomethane (0.29 ml, 4.7 mmol) in tetrahydrofuran (7 ml) was refluxed for 16 hr. On cooling, the mixture was diluted with ethyl ether (20 ml), quenched with methanol (2 ml) and washed with water. Evaporation of the dried (magnesium sulfate) organic phase gave a deep yellow oil, identified as 4-(1-methoxytridecyl)-2-trimethylsilyfuran.
Reaction SMILES: BrCCBr.Br[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[F:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:19][O:20][C:16]=2[CH:15]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:27]2([OH:30])[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][CH2:21][C:18]3[C:17]4[CH:31]=[CH:32][C:14]([F:13])=[CH:15][C:16]=4[O:20][N:19]=3)[CH2:29][CH2:28]2)=[CH:7][CH:8]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC1(c2ccc(Br)cc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To 25 ml of ethyl ether was added 1.0 g of magnenesium turnings, 0.5 ml of 1,2-dibromoethane and a few drops of a solution of 9.4 g of 1,4-dibromobenzene in 50 ml of ethyl ether. The reaction was initiated with heat and maintained by the addition of the solution of 1,4-dibromobenzene. The resultant solution was stirred at ambient temperature for fifteen mins and then a solution of 7.0 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was added with vigorous stirring. After the addition was complete, the mixture was stirred at ambient temperature for thirty mins and then poured into an ice cold solution of ammonium chloride. After dilution with 200 ml of ethyl ether, the organic layer was collected, washed with water (2×), saturated sodium chloride solution and then dried over anyhydrous magnesium sulfate. After filtering, the solvents were evaporated to an oil, which was triturated with petroleum ether. The resultant precipitate was collected and dried to give 4.4 g (41%) of product, mp 138°-145° C. Recrystallization four times from ethyl ether gave the analytical sample, mp 150°-151° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[O:30][C:31]=2[CH3:37])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [Cl-].C([C:5]1([CH2:20][CH2:21][CH2:22][C:23]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)([CH:26]([CH3:28])[CH3:27])[C:24]#[N:25])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7][NH+:6]1[CH3:19])(O)=O.O=P(Cl)(Cl)[Cl:41]>>[Cl-:41].[CH3:38][O:37][C:31]1[CH:30]=[C:29]([C:23]([CH:26]([CH3:28])[CH3:27])([C:24]#[N:25])[CH2:22][CH2:21][CH2:20][C:5]2[CH2:14][C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=3)[CH2:7][N+:6]=2[CH3:19])[CH:34]=[CH:33][C:32]=1[O:35][CH3:36]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(C(C#N)(CCCC2(C(=O)O)Cc3cc(OC)c(OC)cc3C[NH+]2C)C(C)C)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(C#N)(CCCC2=[N+](C)Cc3cc(OC)c(OC)cc3C2)C(C)C)cc1OC

Procedure:
The resulting salt of formula 33 is then decarboxylated to produce a dihydroisoquinolinium salt of formula 34 (step 5). For example, 3-carboxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinolinium chloride (33) is treated with Et2N, followed by POCl3, to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,4-dihydroisoquinolinium chloride (34).