Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC(C)(C)C)=[O:9])=[C:6]([C:15]2[CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[N:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1COCC1>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:15]2[CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH:20]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[N:3]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of di(tert-butyl) 2′-amino-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1,3′ (2H)-dicarboxylate (50.0 mg, 0.09 mmol) in THF (4.5 mL) was added sodium bis(2-methoxyethoxy)aluminum hydride (0.10 mL) dropwise, then stirred for 1 hr at 0° C. The reaction was quenched by an addition of saturated NH4Cl solution, filtered, and washed with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by preparative silica gel TLC (15% acetone in chloroform) to give tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate as a white foam (25 mg, yield 57%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[OH:7][C:3]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[C:4]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:29]1[NH:30][C:31]2[C:27]([C:28]=1[CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:26][CH:25]=[C:24]([CH3:23])[CH:32]=2
Reactant: CC(=O)NCc1c[nH]c2cc(C)ccc12
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Reactant: O=Cc1ccccc1
Product: CC(=O)NCc1c(C(C2=C(O)C(C)(c3ccc(C)cc3)C2=O)c2ccccc2)[nH]c2cc(C)ccc12

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)-acetamide (from Example 10.3) to give the title compound as a pale red solid. MS: 477.3 ([M−H]−).
Reaction SMILES: Cl.Cl.[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([N:14](C(C)C)CC)(C)C.O=[C:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:22][C:23](OC)=[O:24]>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[C:23]([OH:24])=[CH:22][C:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[N:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(O)n(Cc2ccccc2)n1
Yield: 64.2 %

Procedure:
To a suspension of benzylamine dihydrochloride (1.000 g, 5.126 mmol, 1 equiv.) in anhydrous toluene (25 ml) were added successively diisopropylethylamine (1.32 ml, 10.252 mmol, 2 equiv.) and dimethyl 3-oxopentanedioate (0.893 g, 5.126 mmol, 1 equiv.). The resulting mixture was heated at reflux for 18 h before being concentrated in vacuo. The resulting brown oil was purified by flash chromatography over SiO2 (CH2Cl2:MeOH, 97:3). 0.810 g of pure methyl (1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate was obtained as a white solid. Yield 64%. MS (ESI+): 247.1; MS (ESI−): 245.1.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:21][CH2:22][CH3:23])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:7]([NH2:20])[N:6]=1.C1C(=O)N([Br:32])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:32][C:10]1[N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:20])[N:6]=[C:5]([O:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:21][CH2:22][CH3:23])[N:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(C)(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCC(C)(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To 2-[(2,2-dimethylpentyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (372 mg) in dry chloroform (4.05 mL) at 0° C. was added NBS (209 mg) in a single portion. The reaction was warmed to room temperature and was stirred for 5 h. The mixture was taken up into DCM (20 mL) and washed with water (30 mL). The organics were separated and dried using a hydrophobic frit then concentrated in vacuo to afford the title compound as a green/brown viscous foam (475 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([CH2:23][C:24](=[O:26])[N:30]2[CH2:31][CH2:32][N:27]([CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]3=[O:43])[CH2:28][CH2:29]2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccccc2)C1=O
Reactant: O=C1Nc2ccccc2CC1N1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: O=C1Nc2ccccc2CC1N1CCN(C(=O)C[C@@H]2Cc3ccc4[nH]ncc4c3CN(Cc3ccccc3)C2=O)CC1
Yield: 21 %

Procedure:
(S)-2-(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (80 mg, 0.24 mmol) and 3-(piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (75 mg, 0.32 mmol) were reacted in a manner analogous to the preparation of 4-chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 21% yield. MS m/e (M+H)+=543.3. 1H NMR (500 MHz, DMSO-D6): δ=13.01(s, 1H), 10.13(s, 1H), 8.21(s, 1H), 7.36(d, J=8.54, 1H), 7.19(d, J=7.02, 1H), 7.11(m, 2H), 6.90(t, J=7.32, 1H), 6.82(d, J=7.93, 1H), 5.36(d, J=17.40, 1H), 4.61(d, J=17.09, 1H), 3.84(m, 1H), 3.57(d, J=13.12, 1H), 3.47(m, 2H), 3.38(m, 1H), 3.32(M, 1H), 3.09(m, 1H), 3.02(d, J=14.04, 1H), 2.985(m, 2H), 2.85(m, 1H), 2.75(m, 1H), 2.65(m, 3H), 2.50(m, 2H), 2.31(d, J=16.48, 1H), 0.71(s, 9H).
Reaction SMILES: [C:1](Cl)(=O)[CH:2]([CH3:4])[CH3:3].CC(C)(C)C(OC(=O)C(C)(C)C)=O.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:39]3=[CH:40][C:41]4[O:45][CH2:44][O:43][C:42]=4[CH:46]=[C:38]3[O:37][CH2:36]1)[C:24](=[O:35])[N:25]2[CH2:30][C:31](=[N:33][OH:34])[NH2:32].ON=C(N)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:39]3=[CH:40][C:41]4[O:45][CH2:44][O:43][C:42]=4[CH:46]=[C:38]3[O:37][CH2:36]1)[C:24](=[O:35])[N:25]2[CH2:30][C:31]1[N:32]=[C:1]([CH:2]([CH3:4])[CH3:3])[O:34][N:33]=1
Reactant: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NO
Reactant: CC(C)C(=O)Cl
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)=NO
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(Cl)cccc32)no1

Procedure:
Following the procedure as described in EXAMPLE 11.23 and making non-critical variations using isobutyryl chloride to replace trimethylacetic anhydride, and 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide to replace N′-hydroxy-2-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)acetimidamide, 4′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (26%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ7.19 (dd, J=8.0, 8.0 Hz, 1H), 7.00 (dd, J=8.2, 0.8 Hz, 1H), 6.77 (dd, J=7.8, 0.7 Hz, 1H), 6.46 (s, 1H), 6.32 (s, 1H), 5.85 (ABq, 2H), 5.04 (ABq, 2H), 4.95 (ABq, 2H), 3.17 (sep, J=7.0 Hz, 1H), 1.36 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ185.2, 177.1, 165.3, 156.7, 149.2, 143.0, 142.1, 131.6, 130.1, 128.4, 124.6, 116.5, 107.3, 103.1, 101.5, 93.2, 77.1, 58.8, 36.2, 27.5, 20.1, 20.0; MS (ES+) m/z 440.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH:15]=O)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.C([C:27]1[CH:41]=[CH:40][C:30]([CH2:31][N:32]2[C:36]([CH2:37][CH2:38][NH2:39])=[CH:35][N:34]=[CH:33]2)=[CH:29][CH:28]=1)#N.[BH3-][C:43]#[N:44].[Na+]>CO>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:15][NH:39][CH2:38][CH2:37][C:36]3[N:32]([CH:31]([C:43]#[N:44])[C:30]4[CH:29]=[CH:28][CH:27]=[CH:41][CH:40]=4)[CH:33]=[N:34][CH:35]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Reactant: O=C[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#CC(c1ccccc1)n1cncc1CCNC[C@@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-Diphenylethyl)-3(S)-piperidine carboxaldehyde (0.575 g, 1.96 mmol),3-(4-cyanobenzyl) histamine dihydrochloride (0.388 g, 1.30 mmol), and NaCNBH3 (0.123 g, 1.96 mmol) were dissolved in MeOH (15 mL) and stirred at ambient temperature overnight. The solution was concentrated and the residue taken up in EtOAc, washed with sat. NaHCO3 solution, H2O, and brine. The organics were dried, concentrated, and chromatographed (0-4% MeOH/CH2Cl2 /NH4OH) to give the title compound which was isolated as a tris HCl salt. 1H NMR (CD3OD); δ9.05 (s, 1H), 7.81 (d, 2H, J=8 Hz), 7.68 (s, 1H), 7.54 (d, 2H, J=8 Hz), 7.49-7.25 (m, 10H), 5.67 (s, 2H), 4.76-7.74 (m, 1H), 4.05-3.88 (m, 3H), 3.54-3.47 (m, 1H), 3.33-3.30 (m, 1H), 3.19-3.15 (m, 2H), 3.02-3.00 (m, 2H), 2.92-2.90 (m, 2H), 2.42 (br s, 1H), 1.99-1.91 (m, 2H), 1.82-1.78 (m, 1H), 1.31-1.28 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([N:6]3[C:11](=[CH:12]2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)=[N:4][CH:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([N:6]4[C:11](=[CH:12]3)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]4)=[N:4][CH:3]=2)[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: O=C1NCCn2c1cc1cc(O)cnc12
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 1, from 7-hydroxy-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a white solid (42%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:10]=[CH:11][C:12]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7](=O)[C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][NH:38][NH2:39]>>[NH2:35][CH2:36][CH2:37][N:38]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:15]3[C:14](=[O:16])[C:13]4[C:8]([C:7]([C:6]=23)=[N:39]1)=[C:9]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:10]=[CH:11][C:12]=4[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCNN
Reactant: O=C1c2c(Cl)ccc(Cl)c2C(=O)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c21
Product: NCCn1nc2c3c(c(Cl)ccc31)C(=O)c1c(OCc3ccccc3)ccc(OCc3ccccc3)c1-2

Procedure:
2-(2-Aminoethyl)-5-chloro-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one is prepared from 1,4-dichloro-5,8-bis(phenylmethoxy)-9,10-anthracenedione and (2-aminoethyl)hydrazine as described in Example 54 to give the product; mp 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([CH3:11])=[CH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]([CH3:13])[N:3]=1.CCN(C(C)C)C(C)C.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:13])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(=O)[nH]c2c1c(Cl)nn2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1cc(C)c2c(Cl)nn(C)c2n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (720 mg, 3.64 mmol) was dissolved in DMF (5 ml) at rt. Then, DIPEA (1.04 g, 8.0 mmol) and ethyl 2-bromoacetate (0.60 ml, 5.5 mmol) were added and the mixture heated at 90° C. After 1 h, the mixture was cooled to rt, the solvent removed under reduced pressure and the residue purified by column chromatography (eluent 70% hexane in EtOAc) to yield 664 mg (64%) of the title compound. [1H-NMR (DMSO-d6, 400 MHz) δ 6.67 (s, 1H), 4.98 (s, 2H) 4.17 (q, 2H), 3.84 (s, 3H), 2.62 (s, 3H), 1.19 (t, 3H); HPLC-MS RtJ=1.13 min; [M+H]+=284.0, 286.0
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28]Br.[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCBr
Reactant: C1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane and hexahydro-1H-azepine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C>>[OH:1][CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cc[nH]n1
Agent: CN(C)C
Product: OCc1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 60 %

Procedure:
This compound was prepared from 3-(hydroxymethyl)-1 H-pyrazole, [J. Am. Chem. Soc, 71, 3996, (1949)], trityl chloride and trimethylamine using the method of Preparation 18, above. The crude product was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give a white solid (1.428 g, 60%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([NH:17][CH2:18][CH2:19][NH2:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:20][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
5.5 g (39.7 mmol) of 6-chloronicotinonitrile were dissolved in 70 ml of DMSO, and 10.2 g (63.5 mmol) of N-Boc-ethylenediamine and 11 g (79.4 mmol) of potassium carbonate were added. The mixture was stirred at 90° C. for 12 h. The residue was taken up in a mixture of water and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was chromatographed on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 10:1 to 2:1). This gave 7.9 g (77% of theory) of the product as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C:9]([CH3:11])=[CH:10][C:5]=2[CH:4]=1)#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>O.CN1CCCC1=O>[NH:16]1[C:1]([C:3]2[CH:15]=[CH:14][C:6]3[O:7][C:8]([CH3:12])([CH3:13])[C:9]([CH3:11])=[CH:10][C:5]=3[CH:4]=2)=[N:2][N:18]=[N:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=Cc2cc(C#N)ccc2OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1=Cc2cc(-c3nnn[nH]3)ccc2OC1(C)C
Temperature: 150 °C

Procedure:
A mixture of 6-cyano-2,2,3-trimethyl-2H-benzo[b]pyran (see J. Med. Chem., 1991, 34, 3074) (4 g), sodium azide (4.0 g), triethylamine hydrochloride (4.2 g) and 1-methyl-2-pyrrolidinone (40 ml), was heated at 150° C. for 1 hour. On cooling to room temperature water (200 ml) was added and the mixture was brought to pH 14 by the addition of solid sodium hydroxide. The solution was extracted with ethyl acetate (200 ml) then acidified to pH 3-4 with concentrated hydrochloric acid to give a solid which was filtered off, washed with water and dried to give the title compound, 4.5 g, m.p. 179°-181° C. Found: C, 64.58; H, 5.81; N, 23.46; C13H14N4O requires: C, 64.45; H, 5.82; N, 23.13%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Br[CH:16]([C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])[C:17]([O:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C>CC#N>[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C@@H:16]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:17]([O:19][CH3:20])=[O:18])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12].[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C@H:16]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:17]([O:19][CH3:20])=[O:18])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COC(=O)C(Br)c1c(F)cccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](c1c(F)cccc1F)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Product: COC(=O)[C@H](c1c(F)cccc1F)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
tert-Butyl (3R)-piperidin-3-ylcarbamate (0.234 g, 1.168 mmol), methyl bromo(2,6-difluorophenyl)acetate (0.434 g, 1.636 mmol) and DIPEA (0.612 mL, 3.51 mmol) were taken up in MeCN (11 mL) in a 20 mL microwave vial. The reaction was stirred at 90° C. for 18 hours. Room temperature was attained, and the solvent removed in vacuo. Purification of the residue by MPLC (6-50% EtOAc-hexanes) gave (S)-methyl 2-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-2-(2,6-difluorophenyl)-acetate as a yellow gum and (R)-methyl 2-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-2-(2,6-difluorophenyl)acetate as a yellow gum (R,R).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Br:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Br:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-bromobenzenesulfonyl chloride as described in example 2, affording the title compound in 65% yield.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:41][O:40][C:13]2([CH2:36][CH2:35][C@@:34]3([CH3:37])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@:33]3([OH:38])[CH2:32][CH2:31][C@@:30]3([CH3:39])[C@H:19]4[CH2:20][CH2:21]/[C:22]/3=[C:23](/[O:28][CH3:29])\[C:24](OC)=[O:25])[CH2:14]2)[O:12]1.O>C1(C)C=CC=CC=1>[CH2:41]1[CH2:11][O:12][C:13]2([CH2:36][CH2:35][C@@:34]3([CH3:37])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@:33]3([OH:38])[CH2:32][CH2:31][C@@:30]3([CH3:39])[C@H:19]4[CH2:20][CH2:21]/[C:22]/3=[C:23](/[O:28][CH3:29])\[CH2:24][OH:25])[CH2:14]2)[O:40]1
Reactant: COC(=O)/C(OC)=C1\CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CO/C(CO)=C1/CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Under nitrogen a 1M solution of diisobutylaluminium hydride in toluene (0.1 ml) was added to a stirred solution of methyl (20Z)-3,3-ethylenedioxy-9α-hydroxy-20-methoxypregna-5,17(20)-dien-21-oate (112 mg, prepared according to Example 19) in dry toluene (8 ml) at -20° C. The reaction mixture was stirred at -20° C. for 30 minutes. To complete the reaction the same quantity of diisobutylaluminium hydride solution was added and stirring was continued at -20° C. for 5 minutes. Next, water (2 ml) was added and the mixture was stirred at 0° C. for 1 hour. The heterogeneous mixture was filtered, then the filtrate was concentrated under reduced pressure to afford 66 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OCCOS(O)(=O)=O)=[C:5]([C@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[O:12]2)[CH:6]=[C:7]([I:10])[C:8]=1C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1.CN(C)C.[CH2:48]([OH:50])[CH3:49]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[O:12]2)[CH:6]=[C:7]([I:10])[C:8]=1[O:50][CH2:48][CH2:49][S:43][C:40]1[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1cc([C@H]2CC[C@H](c3cc(I)c(C)c(OC)c3OCCOS(=O)(=O)O)O2)cc(OC)c1OC
Reactant: CCO
Agent: CN(C)C
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCSc1ccc(Cl)cc1

Procedure:
trans-2-(3-Methoxy-4-methylsulfoxyethoxy-5-iodophenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (2.5 g, 4.11 mmol) was dissolved in 50 mL ethanol. To this solution was added 4-chlorothiophenol (1.19 g, 8.22 mmol) and trimethylamine (0.831 g, 8.22 mmol). The reaction mixture was refluxed for 16 hours and then the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 3:1 hexane/ethyl acetate)(2.35 g, 87%). 1H NMR (CDCl3): 1.97 (m, 2H); 2.45 (m, 2H); 3.35 (t, 2H); 3.82 (s, 3H); 3.84 (s, 3H), 3.88 (s, 6H); 4.11 (t, 2H); 5.17 (m, 2H), 6.61 (s, 2H); 6.92 (s, 1H); 7.26 (d, 2H); 7.33 (d, 2H); 7.35 (s, 1H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10](NN)=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].C(=N)([O:17]CC)CC.Cl.C(=N)(OCC)CC>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:11])=[O:17])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=N)CC
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)O)cs1
Yield: 103.9 %

Procedure:
2.90 g (14.48 mmol) of 2-guanidino-4-thiazole carboxylic acid hydrazide in 50 ml dry ethanol was slurried with 29.1 mmol of ethyl propionimidate (prepared from 4.0 g (29.1 mmol) of ethyl propionimidate hydrochloride) for 5 days at 25°. The slurry was filtered and the resulting solid was dried for 2 hours at 60° in vacuo to give 2.802 g (75%) of 2-guanidino-4-thiazole carboxylic acid 2-propioniminohydrazide.