Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:30]=[C:29]([NH2:31])[NH:28][N:27]=3)[CH2:22][CH2:21]2)=[N:18][CH:19]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[C:30]4[C:3]([OH:10])([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:31][C:29]=4[NH:28][N:27]=3)[CH2:24][CH2:25]2)=[N:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc(C2CCN(c3ccc(Cl)cn3)CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccc(Cl)cn4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 39.1 %

Procedure:
Ethyl trifluoroacetoacetate (1.28 g, 6.97 mmol) was added to a solution of 3-[1-(5-chloropyridin-2-yl)piperidin-4-yl]-1H-pyrazol-5-amine (0.484 g, 1.74 mmol) produced in Reference Example 20 in acetic acid (8 mL), and the mixture was stirred at 60° C. for 1.5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol=100/0-95/5 (gradient)] and further purified by silica gel column chromatography [elute: hexane/ethyl acetate=20/80-0/100 (gradient)] to obtain the title compound (0.283 g, yield: 39%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[CH:9][C:8]=1[OH:16])=[O:4].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:18]([Cl:17])(=[O:20])=[O:19])[C:8]=1[OH:16])=[O:4]
Reactant: O=C(CCl)NCc1cc2c(cc1O)CCC2
Reactant: O=S(=O)(O)Cl
Product: O=C(CCl)NCc1cc2c(c(S(=O)(=O)Cl)c1O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
70 g (0.29 mole) of 6-(N-chloroacetylaminomethyl)-5-hydroxyindane are dissolved in 150 ml of chlorosulfonic acid, and the mixture is stirred for approx. 30 minutes at room temperature. The mixture is poured into ice water and the product is filtered off with suction. The initially crystalline material becomes oily after a little time and is employed in the next stage in this form without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)[N:3]=1.O.[NH2:16][NH2:17]>O>[NH:16]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)[N:3]=1)[NH2:17]
Reactant: NN
Reactant: Clc1ccnc(-c2cccc(I)c2)n1
Solvent: O
Product: NNc1ccnc(-c2cccc(I)c2)n1

Procedure:
A mixture of 20.7 g of 4-chloro-2-(3-iodophenyl)pyrimidine, 140 ml of water and 80 ml of hydrazine hydrate was heated on a steam bath to produce solution, then refluxed 1/2 hour and allowed to cool overnight. The resulting crystals were collected, washed with methanol:water (1:1) and dried, giving 4-hydrazino-2-(3-iodophenyl)pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)CC1

Procedure:
A solution of 5-nitro-2-chloropyridine (2.50 g) and trans-1,4-cyclohexanediamine (5.40 g) in ethanol (15 ml)tetrahydrofuran (10 ml) was stirred at room temperature for 5 days. The precipitates were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol-concentrated aqueous ammonia (20:4:1)) and crystallized from ethyl acetate to obtain N-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine (Reference Example 3-1 in Table 5).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.O>C(Cl)Cl>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccc2ccccc2c1
Solvent: O
Solvent: ClCCl
Product: c1ccc2cc(Cn3ccnc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of imidazole (15.4 g, 0.226 mol) and 2-bromomethylnaphthalene (22 g, 0.0995 mol) in 200 ml of methylene chloride was stirred at room temperature overnight. The mixture was stirred with 200 ml of water, the organic layer was washed with water (2×200 ml), and stirred with 30 ml of conc. HCl and 200 ml of water. After filtration for the removal of the solid, the methylene chloride layer was discarded, and the aqueous layer was extracted with 200 ml of ether. The above aqueous layer was basified with 3N NaOH solution, extracted with methylene chloride, and the organic layer was dried over magnesium sulfate. The above organic solution was concentrated in vacuo to afford 13.65 g of 1-(2-naphthylmethyl)imidazole, m.p. 87°-88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1Oc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccccc1Oc1ccc(CBr)cc1
Yield: 51.5 %

Procedure:
A solution of the product of Step B (50 mg, 0.205 mmol) NBS (33 mg, 0.9 eq) and AIBN (5 mg, catalytic amount) in CCl4 (2 mL) was heated to reflux for 2 hours, and then concentrated in vacuo. The residue was chromatographed on a flash silica column (20×140 mm) eluted with 5% ethyl acetate/hexane to yield 32 mg (48%) of product (Rf =0.17, 5% ethyl acetate/hexane).
Reaction SMILES: C1(C[O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1OCCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1OCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To a solution of 8.2 g (27 mmol) of 2-[3-(phenylmethoxy)propoxy]isoindoline-1,3-dione, as prepared in the preceding step, in 120 mL anhydrous ethanol under nitrogen was added 1.5 g of 10 wt % Pd/C. Then the nitrogen in the reaction was replaced with hydrogen and the reaction was stirred at room temperature for 5 h. After the reaction was completed, the mixture was filtered through a pad of Celite (diatomaceous earth). The solvent of the filtrate was removed under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate/hexanes (1:1, v/v) as eluent to yield 4.4 g (75%) of white solid as product: 1H NMR (300 MHz, CDCl3) δ7.85-7.81 (m, 2H), 7.78-7.74 (m, 2H), 4.37 (t, J=5.88 Hz, 2H), 3.93 (t, J=5.80 Hz, 2H), 2.55 (br s, 1H), 1.99 (quintet, J=5.86, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O.CN(C)C=O>O>[Cl:14][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cnc1Cl
Temperature: 110 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
5-fluoro-2-hydroxy-3-nitropyridine (11.0 g, 69.4 mmol) prepared in Step 3 was added to a mixed solution of phosphorus oxychloride (38.8 ml, 416 mmol) and N,N-dimethylformamide (537 μl, 6.94 mmol). The reaction mixture was stirred for 5 hours at 110° C. Water (250 ml) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a sodium chloride solution (250 ml) three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate) to give 9.02 g of the titled compound as yellow solid. (Yield: 74%).
Reaction SMILES: [Li].[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]([CH3:18])[CH2:16][CH3:17])C(O)=O)#[N:3].[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([B:19]([OH:22])[OH:20])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]([CH3:18])[CH2:16][CH3:17])#[N:3]
Reactant: CC[C@H](C)COc1ccc(C(=O)O)cc1C#N
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(B(O)O)cc1C#N
Temperature: 25 °C

Procedure:
The experimental procedure for the preparation of the lithium salt was as described in the preparation of compound 43. A solution of trimethyl borate (2.70 g, 0.024 mol) in dry THF (10 ml) was added dropwise to the lithium salt solution. The resultant mixture was allowed to warm to room temperature overnight whilst stirring and dilute hydrochloric acid was then added. The THF/water azeotrope was removed in vacuo and the remaining residue was dissolved in diethyl ether and washed with water until acid-free. The ether was dried (MgSO4) and removed in vacuo to leave a fawn solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 42.4 %

Procedure:
To a 5-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 3-pyridinylboronic acid (29.9 mg, 0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixture was degassed with nitrogen for 10 min. Next was added bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol) and the vial was sealed. The reaction mixture was irradiated (microwave) at 140° C. overnight. The reaction mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse-phase HPLC. The TFA salt of the product was neutralized using saturated NaHCO3, filtered, washed with water and dried under high vacuum to give 33 mg (42%) of product. LCMS E-S (M+H)=417.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.42 (d, J=4.29 Hz, 2H), 5.26-5.43 (m, 1H), 5.91 (s, 1H), 7.62 (dd, J=7.3, 5.0 Hz, 1H), 8.26 (s, 1H), 8.43 (s, 1H), 8.64 (d, J=7.8 Hz, 1H), 8.70-8.79 (m, 1H), 8.96 (br. s., 1H), 9.46 (br. s., 1H), 11.59 (br. s., 1H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[F:18])=O)C1C=CC=CC=1.[CH3:19][O:20][C:21]1[N:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[C@@H:31]1[CH2:33][O:32]1>>[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:33][C@@H:31]([C:24]2[C:23]3[C:28](=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[N:22]=3)[N:27]=[CH:26][CH:25]=2)[OH:32])[CH2:14][CH:13]1[F:18]
Reactant: COc1ccc2nccc([C@@H]3CO3)c2n1
Reactant: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Product: COc1ccc2nccc([C@@H](O)CN3CCC(N)C(F)C3)c2n1

Procedure:
This was prepared from cis-4-benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 2 (7a) and (R)-2-(6-methoxy-[1,5]-naphthyridin-4-yl)oxirane (20d) (100% ee) by the method of Example (20e).
Reaction SMILES: NC1N=C(C(N2CC3C(=CC=CC=3)C2)=O)C2C(=CC=C(C3C=CC=CC=3S(Cl)(=O)=O)C=2)N=1.NCCN(C)C(=O)OC(C)(C)C.[NH2:45][C:46]1[N:55]=[C:54]([C:56]([N:58]2[CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:59]2)=[O:57])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[S:73]([NH:76][CH2:77][CH2:78][N:79](C)[C:80](=O)OC(C)(C)C)(=[O:75])=[O:74])[CH:52]=2)[N:47]=1.Cl>O1CCOCC1>[NH2:45][C:46]1[N:55]=[C:54]([C:56]([N:58]2[CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:59]2)=[O:57])[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[S:73]([NH:76][CH2:77][CH2:78][NH:79][CH3:80])(=[O:74])=[O:75])[CH:52]=2)[N:47]=1
Reactant: CN(CCNS(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(=O)OC(C)(C)C
Agent: CN(CCN)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(=O)(=O)Cl)ccc2n1
Solvent: C1COCCO1
Product: CNCCNS(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
The product is obtained analogously to the preparation of “A64” by reaction of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzenesulfonyl chloride and tert-butyl (2-aminoethyl)methylcarbamate. The resultant tert-butyl (2-{2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzenesulfonylamino}ethyl)methylcarbamate is treated directly with 1 M HCl in dioxane, causing the protecting group to be cleaved. The purification is carried out by means of preparative column chromatography.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24].[OH-:25].[Na+]>O1CCOCC1>[C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:24])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H]1[C@@H](CCCCCc2ccccc2)C(=O)N1OC1CCCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(5-phenyl-1-pentyl)-4-methylazetidin-2-one (140 mg, 0.428 mmol) in dioxane (1.2 mL) is added 1 M aqueous sodium hydroxide (0.64 mL). The solution is stirred at 23° C. for 24 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(5-phenyl-1-pentyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (105 mg, 71% yield).
Reaction SMILES: CCCCC.[H-].[Na+].[CH3:8][N:9]([CH3:28])[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:12][N:11]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C1COCC1>[CH3:28][N:9]([CH3:8])[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([S:24]([NH:27][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])(=[O:25])=[O:26])=[CH:12][N:11]=1
Reactant: CC(C)N=C=O
Reactant: Cc1cccc(Nc2nc(N(C)C)ncc2S(N)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cccc(Nc2nc(N(C)C)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Yield: 97.1 %

Procedure:
Pentane washed sodium hydride (22.0 mmol, 2.05 eq) was suspended in THF (100 mL) and 2-(dimethylamino)-4-[(3-methylphenyl)amino]-5-pyrimidinesulfonamide (3.72 g, 10.74 mmol) was added as a powder over a 30 minute period. After 90 minutes the solidified reaction was loosened by adding more THF (30 mL) followed by adding isopropyl isocyanate (1.09 mL, 11.06 mmole, 2.05 eq). After stirring 90 minutes a small portion of isopropyl isocyanate (150 mL) was added to complete the reaction. The THF was removed under reduced pressure and the residue was dissolved in warm water (100 mL). The pH was adjusted to 4 with acetic acid and the aqueous phase was extracted with four 150 mL portions of ethyl acetate. The organic portions were combined, dried (Na2SO4), decanted and the solvent removed to yield pale yellow crystals (4.11 g, 10.43 mmol, 97%). The crude material was crystallized once from ethanol/water to yield 3.45 g (8.76 mmol, 81%) of pure product, m.p. 178.5°-179° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][O:11][CH2:12][C:6]2=[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=3)=[CH:17][CH:16]=2)[CH:4]=1>C(O)C.CO>[ClH:1].[CH3:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][O:11][CH2:12][C:6]2=[C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:28][N:29]=[N:30][N:31]=3)=[CH:19][CH:20]=2)[CH:4]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCOC2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2c(n1)CCOC2
Reaction time: 18 h

Procedure:
Concentrated hydrochloric acid (0.75 ml) was added to a solution of 7,8-dihydro-2-methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5H-pyrano[4,3-b]pyridine (A1) (0.94 g) in ethanol (6 ml) and methanol (3 ml). The solution was left to stand for 18 hours, and the precipitated solid collected by filtration, and washed with ether to give 7,8-dihydro-2-methyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5H-pyrano[4,3-b]-pyridine hydrochloride (0.47 g), as a white solid, m.p. 173°-175° C.; NMR (d6 -DMSO): 2.7(s,3H), 3.0(t,2H), 3.95(t,2H), 4.7(s,2H), 5.4(s,2H), 7.2(d,2H), 7.4(d,2H), 7.5-7.75 (complex m,5H); 13C NMR (d6 -DMSO): 71.0 (benzylic CH2); mass spectrum (negative fast atom bombardment (-ve FAB), DMSO/Glycerol (GLY)): 398 (M-H)- ; microanalysis, found: C,62.8; H,4.9; N,15.9; H2O, 0.9%; C23H21N5O2.HCl.0.25H2O requires C,62.7; H,5.1; N,15.9; H2O 1.0%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:30][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
A mixture J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-pyrrolidine-1-carboxylate (12.8 g, 31.12 mmol) and ammonium acetate (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system. The layers were separated, and the aqueous layer was extracted with an additional ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of J.7 (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g. 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond.-J1): RT=1.71 min; LC/MS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.10; found 391.96. HRMS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([F:28])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:13]4[C@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)[CH:5]=[C:4]([CH3:29])[N:3]=1.Cl>>[CH3:29][C:4]1[CH2:5][C:6]([C:8]2[C:9]([F:28])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[C@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)([CH3:7])[CH:1]=[CH:2][N:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)cc3c1=O)OC[C@H]2C
Agent: Cl
Product: CC1=NC=CC(C)(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@H]4C)C1

Procedure:
[I; R and R'=H, R"=CH3 ] was prepared by hydrolysis of the ester of part (e) with hydrochloric acid according to the procedure of Example 1(h), and was obtained as a colorless solid, m.p. 308°-312° C. when recrystallized from methanol; [α]D25 =+40.7° (1% in chloroform).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][NH:10][NH2:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:21](OC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][N:10]2[C:21]([OH:26])=[CH:22][C:23]([CH3:25])=[N:11]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CNN)cc1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(C)cc2O)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution containing 2.75 g of (4-methoxybenzyl)hydrazine dihydrochloride in 50 ml of toluene was treated with 1.7 ml of triethylamine at rt and then stirred for 5 min. The mixture was then treated with 1.32 ml of methyl acetoacetate and heated at 100° C. for 15 min. The solvent was evaporated under reduced pressure and then the residue partitioned between dichloromethane/10% citric acid and extracted three times. Combined extracts were washed with brine, then dried over anhydrous magnesium sulphate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography on silica gel using methanol/dichloromethane (1:49) for the elution to give 2.3 g of 2-(4-methoxybenzyl)-5-methyl-2H-pyrazol-3-ol as a white solid. Mass spectrum (ES) m/z 219 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(F)c(F)c1

Procedure:
A solution of 3,4-difluorobenzaldehyde (5.05 g), nitromethane (5.3 mL) and ammonium acetate (6.3 g) in glacial acetic acid (60 mL) is heated at 110° C. for 16 hours, allowed to cool and poured into water (300 mL). The solution is extracted with EtOAc (2×200 mL). The combined extract is washed with 10% NaHCO3, water and dried over sodium sulfate, filtered and evaporated in vacuo to afford 1,2-difluoro-4-(2-nitro-vinyl)benzene (4.2 g). MS: 198 (M+H); 1H NMR (300 MHz, CDCl3) □7.9 (1H, d, J=10 Hz); 7.5 (1H, d, 10 Hz); 7.3 (2H, m); 6.95-7.15 (1H, m).