Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:37]2[N:38]=[N:39][NH:40][N:41]=2)[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:37]2[N:38]=[N:39][N:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=3)[N:41]=2)[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(-c2nn[nH]n2)cc(OCc2ccccc2)c1OCc1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nnn(-c3ccc(C(F)(F)F)cn3)n2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
2-chloro-5-(trifluoromethyl)pyridine (0.181 g, 1.00 mmol) was added to a stirred suspension of 5-(3,4-bis-benzyloxy-5-nitro-phenyl)-2H-tetrazole (0.4 g, 1.00 mmol) and potassium carbonate (0.14 g, 1 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature till completion, then diluted with dichloromethane and washed with water. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to leave a crude residue that was recrystallised from a dichloro-methane/isopropanol mixture to afford 2-(5-(3,4-bis(benzyloxy)-5-nitrophenyl)-2H-tetrazol-2-yl)-5-(trifluoromethyl)pyridine, 0.389 g (71%).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]3[C:20](=[C:21]([C:22]4[CH:27]=CC(O)=[CH:24][CH:23]=4)[C:11]=2[C:10]=1[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16]3.Cl>N1C=CC=CC=1>[CH3:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]3[C:20](=[C:21]([C:22]4[CH:27]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:24][CH:23]=4)[C:11]=2[C:10]=1[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16]3
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)cc3)c2c1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1
Yield: 87.4 %

Procedure:
Acetic anhydride (0.68 mL, 7.20 mmol) was added to a 0° C., stirred solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 6.57 mmol) in pyridine (8.6 mL). After 17 h the reaction mixture was added to 5% aqueous HCl and the resulting solid was filtered and washed with 5% aqueous HCl, water and triturated with pet. ether. It was then dried in vacuo to provide the title compound as a white solid (1.99 g, 88%): mp: 147-150° C.; NMR (DMSO-d6); δ8.49 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.46 (ddd, J=8, 6, 2, 1H), 7.38 (ddd, J=8, 1, 1 Hz, 1H), 7.39-7.34 (m, 2H), 7.28 (d, J=8 Hz, 2H), 6.90 (d, J=9 Hz, 2H), 2.40 (d, J=1 Hz, 3H), 2.34 (s, 3H), 1.57 (d, J=1 Hz, 3H); MS (EI): 346 (90%, MI), 304 (100%); Anal. Calc. for C22H18O2S: C, 76.27; H, 5.34; N, 0.00. Found: C, 75.88; H, 5.04; N, 0.28.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][CH:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-phenylpiperidine (141.68 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (100:1). This resulted in 92.9 mg (49%) of methyl 2-phenyl-3-(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH:40]1([Mg]Br)[CH2:42][CH2:41]1.C(OCC)(=O)C>O1CCCC1>[CH:40]1([C:37]([OH:39])([CH3:38])[CH2:36][O:35][C@H:32]2[CH2:31][CH2:30][C@H:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:11][CH:10]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][CH:28]=[C:4]34)[CH2:34][CH2:33]2)[CH2:42][CH2:41]1
Reactant: Br[Mg]C1CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ccnn12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C3CC3)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.30 g) in tetrahydrofuran (3 mL) was added dropwise cyclopropylmagnesium bromide (0.5M tetrahydrofuran solution, 2.3 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.22 g, 68%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[O:35][N:34]=[C:33](C2C=CC(N)=CC=2)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:33]3[N:32]=[C:31]([CH3:30])[O:35][N:34]=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cc1nc(-c2ccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cc2)no1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(5-methyl-1,2,4-oxadiazol-3-yl)aniline in step 1. MS: 409.5 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CSc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CSc1ccc(C(=N)Nc2ccc(C(C)(C)C)cc2)cc1
Yield: 62.13 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (1 g, 6.7 mmol) and 4-tert-butylaniline (1 g, 6.7 mmol) by following the procedure described in preparation 10 (1.24 g, yield 62.13%, purity 98.67% by HPLC). 1H-NMR (CDCl3):δ 1.32 (s, 9H), 2.51 (s, 3H), 4.81 (bs, 2H, D2O exchangeable), 6.90-6.92 (d, 2H), 7.26-7.29 (m, 2H), 7.35-7.37 (m, 2H), 7.78-7.8 (d, 2H). MS m/z:299.4 (M+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH2:25]1[O:27][CH2:26]1>C1COCC1>[OH:27][CH2:26][CH2:25][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C1CO1
Reactant: N#Cc1ccc(-c2cc3ccc(Br)cc3cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc3ccc(CCO)cc3cn2)cc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
The product from Example 74A (4 mmol) is dissolved in 20 mL THF and is cooled to −60° C. under nitrogen. n-BuLi (4.4 mmol) is added dropwise, and the mixture is stirred at −60° C. for additional 30 minutes. A solution of ethylene oxide (20 mmol) in 10 ml THF is added and the mixture is allowed to warm to 10° C. and is stirred to complete the reaction. The mixture iss cooled back down to 0° C. and is slowly quenched with 2N HCl to pH=3. The solvent is removed under vacuum and the residue is dissolved in 20 mL methylene chloride, is washed with water, and is concentrated under reduced pressure. The residue is chromatographed on silica gel (5:95 MeOH:CHCl3) to provide the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:21][CH:10]1[CH:11]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CCC1OC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC1CNCCC1OC(=O)C(C)(C)C
Reaction time: 20 h

Procedure:
Palladium hydroxide (20% on carbon, 1.5 g) is placed in a round-bottom flask under an argon atmosphere and covered with methanol, A solution of 2,2-dimethyl-propionic acid (3RS,4RS)-1-benzyl-3-methyl-piperidin-4-yl ester (4) (15 g, 51.8 mmol) in 300 ml of methanol is added, followed by an 1.3M methanolic HCl solution (62 ml, 78 mmol). Then the mixture is hydrogenated under normal pressure for 20 h. The solution is filtrated through celite and evaporated under reduced pressure. The residue is dissolved in diethyl ether and washed with 1N aqueous sodium hydroxide solution and brine. The combined organic layers are dried over Na2SO4 and evaporated under reduced pressure.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[CH3:2])[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: Cc1ccncc1-c1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cnccc2C)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Yield: 12.9 %

Procedure:
To a mixture of 5-(4-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 11, 605 mg, 2.53 mmol) and K2CO3 (349 mg, 2.53 mmol) in DMF (10 ml), 3-bromo-1,1dimethoxy-propane (399 μl, 2.78 mmol) was added in two portions over 2 days and the mixture was contemporarily stirred at room temperature. Water was then added and washed with Et2O, the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-02) to give 100 mg of the title compound (27% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1F
Yield: 82 %

Procedure:
To a solution of 2-fluoro-3-methyl benzoic acid (3.57 g, 23 mmol) in MeOH (40 mL) was added concentrated sulfuric acid (2.3 mL), and the reaction mixture was heated at reflux for 12 h. The reaction mixture was cooled, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with a saturated solution of NaHCO3 and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford methyl 2 fluoro-3-methylbenzoate as a yellow oil (3.2 g, 82%): 1H NMR (300 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.08 (t, J=8 Hz, 1H), 3.98 (s, 3H), 2.31 (d, J=3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:17][C@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add cold trifluoroacetic acid (600 ml) (ice bath) to N-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl](S)-alanine, t-butyl ester (25.5 g) and stir the resulting mixture at room temperature under a nitrogen atmosphere for 4 hours. Concentrate the solution in vacuo to give a viscous oil. Triturate the viscous oil with hexane (3 l) and then ether to yield N-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:19]1[CH2:22][CH2:21][CH:20]1[C:23](=N)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-:32].[Na+]>CO>[CH:6]([N:19]1[CH2:22][CH2:21][CH:20]1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Add 68 ml of 3.6 N aqueous sulfuric acid to a stirred solution of 40.0 g of 1-benzhydryl-2-benzimidoylazetidine in 800 ml. of methanol. Stir under a nitrogen atmosphere for 1.5 hours at room temperature. Slowly pour the mixture, with continuous stirring, into 234 ml. of 1.1 N aqueous sodium bicarbonate. Filter the resultant solid, and extract the filter cake with methylene chloride. Combine the methylene chloride extracts with the methanolic filtrate and remove all solvent in vacuo. Dissolve the residual solid in ether, wash with water, and dry over anhydrous sodium sulfate. Remove the drying agent, concentrate the solution in vacuo to a volume of 350 ml. and triturate the solid which precipitates. Filter to obtain the analytically pure product, m.p. 114°-115° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:33]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(F)cc1F

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: CO[C:3](=[O:5])O.[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[CH2:20][C@@H:19]([CH2:21][OH:22])[CH:18]=[CH:17]2)=C(Cl)[N:8]=1.[OH-].[Na+]>O>[NH2:6][C:7]1[NH:8][C:3](=[O:5])[C:10]2[N:11]=[CH:12][N:13]([C@H:16]3[CH2:20][C@@H:19]([CH2:21][OH:22])[CH:18]=[CH:17]3)[C:14]=2[N:15]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Reactant: COC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C=C[C@H](CO)C2)c(=O)[nH]1
Temperature: 75 °C

Procedure:
To a 5 mL round-bottom flask equipped with a reflux condenser is added cis-2-amino-6-chloro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine methylcarbonate as prepared in Example 3 (10 mg, 0.03I mmol), sodium hydroxide (2.5 mg, 0.062 mmol), and deionized water (1 mL). The resultant heterogeneous mixture is heated at 75° C. for 12 hours. The reaction mixture becomes a pale amber solution which is filtered hot through a bed of diatomaceous earth. The pH of the filtrate is adjusted to pH 7 with 1N hydrochloric acid. Acetonitrile is added and the solution is concentrated in vacuo to a solid via azeotropic removal of water. The solid is tritriated with 2 mL of methanol and the solution is filtered. The filtrate is concentrated in vacuo to give cis-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl ]-6H-purine-6-one as a white solid which exhibits the following physical data: IR (nujol mull, cm-1) 3500- 3600 (br, m), 1725 (m), 1630 (s), 1605 (s); UV (EtOH, nm) λmax=275, 255; λmin=225; and mp 268-270° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 54.4 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (5.6 g), 4-bromophenol (9.87 g) and triethylamine (19.89 ml) was stirred at 120° C. for 15 hr, and ethyl acetate was added. The reaction mixture was washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A solid precipitated from the residue was collected by filtration to give the title compound (5.77 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)[N:9]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.90) (0.392 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.409 g, 77%). MS (ISP) 531.3 [(M+H)+]; mp 156° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[CH:11][CH:10]=1>CO>[C:1]([C:2]1[N:14]=[C:13]([C:12]2[CH:17]=[CH:18][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[NH:15][CH:3]=1)([O:5][CH3:6])=[O:4]
Reactant: COc1ccc(C(N)=NO)cc1
Reactant: C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1c[nH]c(-c2ccc(OC)cc2)n1
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A solution of methyl propiolate (25.4 g, 0.3 mol), p-methoxybenzamidoxime (50 g, 0.3 mol) and CH3OH (700 ml) was heated at reflux with stirring. After 8 hours, the reaction mixture was concentrated to dryness, and the residue treated with diphenyl ether (300 ml) and heated at reflux. After 2.5 hours, the reaction mixture was poured in C6H14 (2 L) and allowed to stand. The C6H14 was decanted off and the residue chromatographed on silica gel. The product was eluted with 2% CH3OH--CHCl3 to yield 21 g (30%) of 63; m.p. 188°-90° C. (trituration with Et2O). Analysis calculated for C12H12N2O3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1.O1CCOCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:19][CH:18]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Clc1ccc(Nc2ccc(C3CNCCO3)cc2)nc1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
To a stirred solution of (RS)-2-[4-(5-chloro-pyridin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (50 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.26 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford (RS)-(5-chloro-pyridin-2-yl)-(4-morpholin-2-yl-phenyl)-amine (19 mg, 51%) as a white solid. MS (ISP): 292.1 ([{37Cl}M+H]+), 290.1 ([{35Cl}M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([NH:13][CH3:14])[CH:10]([OH:15])[CH2:9]2)=[N:6][CH:7]=1.[CH:16](=O)[C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+].C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]3[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=3)[CH3:14])[C@H:10]([OH:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: CNC1CN(c2ccc(Br)cn2)CC1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(C)[C@@H]2CN(c3ccc(Br)cn3)C[C@H]2O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Dissolve 1-(5-bromo-pyridin-2-yl)-4-methylamino-pyrrolidin-3-ol (0.347 g, 1.28 mmol) in dichloroethane (10 mL) and add veratraldehyde (212 mg, 1.28 mmol), sodium triacetoxyborohydride (405 mg, 1.91 mmol) and acetic acid (125 mL, 2.18 μmol). Stir the mixture at room temperature overnight. Dilute with saturated sodium bicarbonate and extract the mixture with dichloromethane (3×). Dry the combined organic portions over sodium sulfate, filter, and evaporate. Purify the resulting residue by silica gel chromatography, eluting with 0-9% methanol (2N NH3)/CH2Cl2 to give 390 mg (72%) of the title compound as a white solid. MS/ES m/z (81Br) 424.0 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:33][CH:34]=2)[S:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1sc(S)nc1C
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (385 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [4-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]thiazol-5-yl]acetate (750 mg, yield 82%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).