Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[OH:23])=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
To a solution of {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (227 mg, 0.589 mmol) in chloroform (10 mL) was added manganese dioxide (454 mg, 5.22 mmol). The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated to provide {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanone (200 mg, 89%) as a white solid. Rf 0.30 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.58 (d, 1H), 8.40 (d, 1H), 8.16 (d, 1H), 8.00 (d, 2H), 7.61 (t, 1H), 7.55–7.38 (m, 3H), 7.01 (t, 1H), 6.75 (d, 1H), 5.02 (d, 1H), 4.18 (m, 1H), 1.96 (m, 2H), 1.70–1.41 (m, 6H); MS m/z 384 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-:15].[K+].OO>CO.C(=O)([O-])[O-].[K+].[K+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)(=[O:15])[NH2:2]
Reactant: O=C([O-])O
Reactant: CC(=O)CCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(=O)CCc1ccc(C(N)=O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 9.70 g (0.056) mole of 4-(4-cyanophenyl)-2-butanone (the product of step (a)) in 15 ml of methanol, 1.80 g of potassium bicarbonate and 0.20 g of potassium carbonate were added. To the resulting mixture, 10.0 ml (0.088 mole) of 30% hydrogen peroxide was added dropwise over an hour. The reaction mixture was stirred for 24 hours and then chilled. The solid was collected by filtration, was rinsed twice with water and was dried to give 9.67 g of the above-identified product, melting point 152°-154° C. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[S:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[S:19])[CH:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[O:30])[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=S
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=S)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-thione and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 229°-231° C. (d).
Reaction SMILES: Cl.[C:2]([C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:20]>>[C:2]([C:10]1[CH:11]=[C:12]([C:18]([NH2:19])=[O:20])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)c1ccccc1
Agent: Cl
Product: Cc1[nH]c(=O)c(C(N)=O)cc1C(=O)c1ccccc1

Procedure:
Admix 80 ml 35% hydrochloric acid and 20 g (0.078 mole) of 5-benzoyl-1,2-dihydro-6-methyl-2-oxo-3-pyridine carbonitrile, stir the mixture at 40° C. for 5 hours, cool, and dilute the resulting mixture with 80 ml water. Collect the title compound as a precipitate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)=[N:8]1.Br[C:46]1[CH:51]=[N:50][CH:49]=[C:48]([CH:52]2[CH2:54][CH2:53]2)[N:47]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:52]1([C:48]2[N:47]=[C:46]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[C:9]4[C:25]3[N:30]=[C:29]([O:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]4)[CH:28]=[N:27][CH:26]=3)[CH:51]=[N:50][CH:49]=2)[CH2:54][CH2:53]1
Reactant: Brc1cncc(C2CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(B5OC(C)(C)C(C)(C)O5)cc34)n2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cncc(C6CC6)n5)cc34)n2)C1
Temperature: 100 °C
Yield: 70 %

Procedure:
A glass microwave reaction vessel was charged with (3R)-tert-butyl 3-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (1.315 g, 2.17 mmol) and Pd(PPh3)4 (0.125 g, 0.11 mmol). The tube was sealed and evacuated under vacuum and back-filled with N2 (g). A solution of 2-bromo-6-cyclopropylpyrazine (0.562 g, 2.82 mmol) in dioxane (1.8 mL) and 2 M Na2CO3 (5.43 mL, 10.86 mmol) were added. The reaction mixture was stirred and heated at 100° C. for 2 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.910 g, 1.52 mmol, 70% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 598.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:29]=[CH:28][C:22]3[C:23](=[O:27])[CH:24]=[CH:25][O:26][C:21]=3[C:20]=2[CH2:30][CH2:31][CH2:32]C2C=CC=CC=2)=[CH:10][CH:9]=[CH:8][C:7]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].O1C2C(=CC=CC=2)C(=O)C=C1>[Pd].CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:7]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH3:32]
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(=O)ccoc3c2CCCc2ccccc2)c1CCC(=O)OC
Agent: [Pd]
Agent: O=c1ccoc2ccccc12
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)OC)c2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 38 %

Procedure:
A 1.0 g (1.49 mmol) sample of 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-[[4-oxo-8-(3-phenylpropyl)-4H-1-benzopyran-7-yl]oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example was catalytically hydrogenate over 10% palladium on carbon, in 30 mL of 1:1 methanol-ethyl acetate, at room temperature and 1 atmosphere, using thin layer chromatography to monitor the reduction of the starting chromone. The catalyst was filtered and the filtrate was concentrated in vacuo giving an oily product which was purified by flash-chromatography. There was obtained 0.38 g (38%) of the title chromanone as a colorless oil.
Reaction SMILES: CO[CH2:3][CH2:4]OC.Br[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:9]=1.C(B1OC(C)(C)C(C)(C)O1)=C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:10]2[CH:9]=[C:8]([CH:3]=[CH2:4])[CH:20]=[CH:19][C:11]=2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:23][CH:24]=1
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
To a mixed solution of ethylene glycol dimethyl ether 50 mL and water 15 mL of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 5.0 g were added vinylboronic acid pinacol ester 2.7 mL, potassium carbonate 2.3 g and tetrakis(triphenylphosphine)palladium(0) 0.80 g at room temperature sequentially, and it was heated and refluxed under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, toluene and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=20:1] to give tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 3.4 g of yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([N:9]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)[CH3:10])=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][NH:30][CH2:31][CH2:32][CH2:33][OH:34]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18](=[O:20])[N:30]([CH2:31][CH2:32][CH2:33][OH:34])[CH3:29])[CH2:16][CH2:17]2)[CH3:10])=[CH:21][CH:22]=1
Reactant: CNCCCO
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C(=O)N(C)CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
A solution of 0.09 g (0.276 mmol) of trans-4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 2.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF. 0.026 mL (0.304 mmol, 1.1 eq) of oxalyl chloride was added within 5 min and stirring was continued for 90 min. The solution was evaporated, redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.197 mL (2.21 mmol, 7.2 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (1986), (4), 338-40]at 0° C. The reaction was kept over night at RT, then partitioned between Et2O (×3)/aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 5 g silica gel (EtOAc:CH2Cl2 1:9 to 9:1) gave 0.064 g (58%) of pure trans-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexylmethyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 397 (MH+, 1Cl).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12.[I:16]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[C:14]([I:16])[S:15][C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Product: CCOC(=O)c1cnc2cc(I)sc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a stirring solution of ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate (Elliot, R. L, O'Hanlon, P. J., Rogers, N. H. Tetrahedron 43 (14) 3295-3302 (1987)) (2.50 g, 10.96 mmol) in trifluomethanesulfonic acid (50 mL) at 0° C. was added N-iodo succinimide (2.46 g, 10.96 mmol) portion wise. The mixture was stirred for 1 hour, allowing the solution to warm to ambient temperature. Ice (50 g) was added and the resulting aqueous extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried over MgSO4 and solvent removed to afford 2.92 g title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:10]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:9]1)=O)(C)(C)C.[ClH:37]>C(O)C>[ClH:37].[CH3:36][S:33]([C:29]1[CH:28]=[C:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:22]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1N1CCNCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
3-(3′-methanesulfonyl-biphenyl-3-yl)-4-o-tolyl-piperazine-1-carboxylic acid tert-butyl ester (90 mg) in ethanol (1 mL) was treated with a saturated solution of HCl in ethanol (1 mL) at room temperature overnight. The solution was concentrated in vacuo to yield crude 2-(3′-methanesulfonyl-biphenyl-3-yl)-1-o-tolyl-piperazine hydrochloride, MS: 407.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:11][CH3:12])=[N:9][NH:10][C:4]=2[CH:3]=1.[CH3:13][N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:16]([NH:25][C:26]([NH2:28])=[O:27])[CH2:15]1.CC(C)([O-])C.[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1COCC1>[CH3:12][O:11][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:28][C:26]([NH:25][C@H:16]3[C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:18][N:14]([CH3:13])[CH2:15]3)=[O:27])=[CH:3][C:4]=2[NH:10][N:9]=1
Reactant: CN1C[C@@H](NC(N)=O)[C@H](c2ccccc2)C1
Reactant: COc1n[nH]c2cc(Cl)ncc12
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1n[nH]c2cc(NC(=O)N[C@@H]3CN(C)C[C@H]3c3ccccc3)ncc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
6-Chloro-3-methoxy-1H-pyrazolo[4,3-c]pyridine (50 mg, 0.272 mmol), 1-((3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl)urea (Intermediate 17B; 90 mg, 0.409 mmol), BrettPhos pre-catalyst (21.75 mg, 0.027 mmol), and potassium tert-butoxide (1 M in THF, 0.817 mL, 0.817 mmol) were dissolved in THF (1 mL). The vial was degassed with argon for 5 min and the reaction stirred at 60° C. for 16 h. The reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (0-20% CH2Cl2/MeOH with 1% ammonia) gave 1-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-[(3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl]urea. MS ESI calc'd. For C19H22N6O2 [M+1]+ 367. found 367. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 7.72 (s, 1H), 7.43 (s, 1H), 7.31-7.26 (m, 3H), 7.22-7.18 (m, 2H), 4.22-4.14 (m, 1H), 3.98 (s, 3H), 3.16-3.04 (m, 1H), 2.64-2.58 (m, 2H), 2.48 (s, 3H), 2.38-2.28 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([C@H:7]([NH2:11])[C:8](O)=[O:9])=[CH:5][CH:4]=[C:3]([Cl:12])[CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:11][C@@H:7]([C:6]1[CH:5]=[CH:4][C:3]([Cl:12])=[CH:2][CH:1]=1)[CH2:8][OH:9]
Reactant: N[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)c1ccc(Cl)cc1

Procedure:
A mixture of L-4-chloro-phenylglycine (1.74 g, 9.37 mmol) and LAH (712 mg, 18.75 mmol) in THF (40 mL) is refluxed for 1.5 h. After completion, the reaction mixture is quenched by Na2SO4.10H2O and the product is isolated by filtration with Celite, washed with THF and dried under reduced pressure to give the title compound as oil; HPLC: AtRet=1.46 min; 1HNMR (DMSO-d6) 7.35 (d, 2H), 7.30 (d, 2H), 4.80 (bs, 1H), 3.85-3.80 (m, 1H), 3.45-3.20 (m, 2H), 1.85 (bs, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(NS(C)(=O)=O)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)c1ccc(NS(C)(=O)=O)c(N)c1
Yield: 83 %

Procedure:
Ethyl 3-nitro-4-[(methylsulfonyl)amino]benzoate (1.0 g, 0.0035 mol) was dissolved in ethanol (40 mL) and hydrogenated at 20 psi in the presence of platinum oxide (Aldrich, 0.02 g) for 1 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to 20 mL. On cooling, a precipitate formed which was separated by filtration, washed with cold ethanol, and dried to give 0.75 g (84%) of ethyl 3-amino-4-[(methylsulfonyl)amino]benzoate as a white powder, mp 151° C.
Reaction SMILES: [CH2:1]([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)[CH2:2][CH2:3][CH3:4].C1(N)CCC1>CN1CCCC1=O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:16]2[C:15]([NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:29][CH:28]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Agent: NC1CCC1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2NC2CCC2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with cyclobutylamine ([2516-34-9]) in N-methyl 2-pyrrolidone for 3 days at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=298.4 [M+H+].
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][C:3]=2[O:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: OCCCc1ccc2c(c1)OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCc1ccc2c(c1)OCO2
Yield: 80.2 %

Procedure:
To a mixture of 3-(3,4-methylenedioxyphenyl)propyl alcohol (0.26 g, 1.4 mmoles) and celite in CH2Cl2 (7 ml) was added PCC (0.46 g, 2.2 mmoles). The brown reaction mixture was filtered through a plug of celite 1.5 hours later and then concentrated. The brown residue was subjected to flash chromatography (20% EtOAc/hexanes) to provide 0.20 g (77%) of the title compound as a light yellow oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]([O:13][CH2:14][Cl:15])=[O:12].[CH2:16]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18].Cl>C1(C)C=CC=CC=1>[CH2:16]([N:20]([CH:21]([CH3:23])[CH3:22])[C:11](=[O:12])[O:13][CH2:14][Cl:15])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CNC(C)C
Reactant: O=C(Cl)OCCl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)OCCl)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Toluene (9 ml), 1.42 ml of N,N-diisopropylethylamine, and 0.56 ml of chloromethyl chloroformate were added in that order to 870 mg of N-isobutylisopropylamine, and the mixture was stirred at room temperature for 16 hr. 1 N hydrochloric acid (15 ml) was added thereto, followed by separation. The organic layer was washed with 15 ml of a 5% aqueous sodium hydrogencarbonate solution and 15 ml of 20% brine, was dried over anhydrous magnesium sulfate, and was filtered. The solvent was removed by distillation under the reduced pressure to give 1.23 g of chloromethyl N-isobutyl-N-isopropylcarbamate.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[OH:17])[CH:2]([CH2:4][OH:5])[OH:3].C(=O)([O-])O.[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CS(C)=O>[CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[O:17][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOC1=C(OCC(O)CO)[C@@H]([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Under an argon atmosphere, 3-O-glyceryl ascorbic acid (5.10 g) obtained in Example 1 was stirred in DMSO (20 mL), and further, sodium hydrogen carbonate (1.71 g) was added and the mixture was stirred at room temperature for 30 minutes. Thereafter, hexadecyl bromide (9.42 g) was added and the mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 13.6 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.4), and concentration was performed under reduced pressure to obtain 3-O-glyceryl-2-O-hexadecyl ascorbic acid (4.09 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[CH:15]1)([O-])=O>CCO.[Ni]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[CH:15]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cnc(CO)c1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1-n1cnc(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol (167 mg, 0.58 mmol) in EtOH (10 mL) was added a slurry of Raney Nickel (500 mg, washed, wet). The mixture was allowed to stir at room temperature overnight. Upon completion, the reaction mixture was filtered through Celite and concentrated to afford (1-(2-amino-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol. MS m/z=258 [M+H]+. Calc'd for C11H10F3N3O: 257.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)=[O:4].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2OC)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)cc(-c2ccccc2OC)c1
Reaction time: 18 h
Yield: 98.2 %

Procedure:
2′-Methoxy-5-nitro-biphenyl-3-carboxylic acid methyl ester (8.2 g, 28.5 mmol) and SnCl2 dihydrate (35 g) in EtOAc (300 mL) was heated to reflux and stirred for 18 hours, then cooled and stirred at room temperature for 48 hours. Saturated aqueous NaHCO3 was added until the aqueous portion of the mixture reached pH 10. The organic layer was separated, and the aqueous layer was washed with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give 7.2 g of 5-amino-2′-methoxy-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=258.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: NCCCO
Reactant: O=C(O)c1cc2ccccc2o1
Product: O=C(NCCCO)c1cc2ccccc2o1
Yield: 20.6 %

Procedure:
2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and 3-amino-1-propanol (2.83 ml, 37 mmol) were coupled according to the procedure of example 22 to provide 1.39 g (17.2% yield) of the desired product as a yellow solid. Electrospray Mass Spec: m/z 219.8 (M+H)+.