Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(aminomethyl)piperidine-1-carboxylate (0.611 g, 2.851 mmol) and diisopropylethylamine (0.479 g, 3.706 mmol) were dissolved in 30 mls of dry dichloromethane. To this mixture was added benzyl chloroformate (0.552 g, 3.136 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 mls of dichloromethane, washed once with 1N aqueous HCl, one with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure to 950 mgs (96%) of the title compound and used directly without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[N+:13]([O-])[CH:14]=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([Cl:28])(=O)=O)=CC=1>O1CCOCC1>[ClH:28].[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[CH2:17][Cl:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc[n+]([O-])cc1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Product: Cl
Product: O=C(OCc1ccccc1)c1cnccc1CCl

Procedure:
A mixture of the title compound of Preparation 7 (1.8 g, 7.3 mmol), p-toluenesulfonylchloride (2.0 g, 11 mmol) and dioxane (10 ml) was heated under reflux for 1.5 hours. The reaction mixutre was cooled to 0° C., diluted with water, treated with solid NaHCO3 and extracted with diethyl ether. The ether extracts were combined, dried (Na2 SO4), filtered and treated with HCl gas. The precipitate was filtered and washed with diethyl ether to afford 1.4 g of the title compound of this preparation. mp 149°-151° C. 1H NMR (CDCl3): δ 5.27 (2H, s), 5.42 (2H, s), 7.32-7.39 (5H, m), 8.35 (1H, d, J=6), 8.91 (1H, d, J=6), 9.28 (1H, s).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N)C[C@@H]12

Procedure:
5.0 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol, 100 ml methanol, 10 ml of 80% hydrazine hydrate and 4 spatula tips of Raney nickel are heated for 30 min on a water bath. Purification and recrystallization are performed as described for the purification of 16α-amino-3-methoxy-estra-1,3,5(10)-triene-17β-ol. Yield: 3.2 g (69%). F=158-161° C.; [α]D+41° (pyridine). IR: 3367 (NH). 3601 (OH);
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)C.C(O[N:22]=O)CC(C)C>C(OCC)C>[S:1](=[O:3])(=[O:2])([O-:5])[O-:4].[C:7]1([N+:6]#[N:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:7]1([N+:6]#[N:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(O)O
Reactant: CC(C)CCON=O
Solvent: CCOCC
Solvent: CCO
Product: N#[N+]c1ccccc1
Product: O=S(=O)([O-])[O-]

Procedure:
Concentrated sulfuric acid (50 mL, 96%) was slowly dropped into a solution of aniline (30 g. 0.32 mol) ill ethanol (280 mL) until the white precipitate newly formed disappeared again at 0-5° C. To this mixture, isoamylnitrite (40 g, 0.34 mol) was slowly added with stirring. An equal volume of ethyl ether was added to precipitate the product. The mixture was filtered and the residue washed with ethanol:ether (1:1, v/v) to provide a crude greenish solid of benzenediazonium sulfuric acid salt for the following reaction.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(=O)(O)O.[NH2:11][NH:12][C:13]([NH2:15])=[NH:14].C(=O)=O>O>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[NH2:11][NH:12][C:13]([NH2:15])=[NH2+:14].[NH2:11][NH:12][C:13]([NH2:15])=[NH2+:14]
Reactant: N=C(N)NN
Reactant: O=C(O)C(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NNC(N)=[NH2+]
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Oxalic acid (2.00 g, 22.20 mmol) was dissolved in 40 ml of distilled water. Aminoguanidine bicarbonate (6.05 g, 44.40 mmol) was added via syringe at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 24 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:12]([C:13]2[S:14][C:15](Br)=[CH:16][CH:17]=2)=[C:11]2[C:7](=[C:8]([C:24]3[S:25][C:26](Br)=[CH:27][CH:28]=3)[N:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]2=[O:19])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[Cu][C:32]#[N:33].[CH3:34][N:35](C=O)C>>[CH2:1]([N:5]1[C:12]([C:13]2[S:14][C:15]([C:34]#[N:35])=[CH:16][CH:17]=2)=[C:11]2[C:7](=[C:8]([C:24]3[S:25][C:26]([C:32]#[N:33])=[CH:27][CH:28]=3)[N:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]2=[O:19])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C2=C(c3ccc(Br)s3)N(CCCC)C(=O)C2=C1c1ccc(Br)s1
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Product: CCCCN1C(=O)C2=C(c3ccc(C#N)s3)N(CCCC)C(=O)C2=C1c1ccc(C#N)s1

Procedure:
The synthesis of 2,5-di-n-butyl-3,6-bis(5-bromo-thiophen-2-yl)pyrrolo[3,4-c]-pyrrole-1,4-dione is described in Zhou et al., Macromolecules 43 (2010) 821-826. 2,5-Di-n-butyl-3,6-bis(5-bromo-thiophen-2-yl)pyrrolo[3,4-c]-pyrrole-1,4-dione (1.08 g, 1.89 mmol) and copper(I)-cyanide (4.00 g, 44.6 mmol) in dry DMF (15 mL) are heated under argon at 130° C. for 315 min and at 165° C. for 40 min. The solvent is removed under reduced pressure and the crude product continuously extracted from the reaction mixture with chloroform. The extract is purified by column chromatography (dichloromethane) and washed with hexane affording 333 mg (38%) of a dark violet solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:2]1.[C:16]1([C:22]2[O:26][C:25]([C:27](OCC)=[O:28])=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][N:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:27]([C:25]3[O:26][C:22]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:23][N:24]=3)=[O:28])[CH2:4]2)=[CH:11][CH:10]=1)[CH3:15]
Reactant: CN(C)Cc1ccc(OC2CNC2)cc1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Product: CN(C)Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Yield: 38 %

Procedure:
Using a similar protocol as described in Example 16 employing 33B (0.10 g, 0.48 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.12 g, 0.53 mmol) as starting materials afforded 69 mg (38%) of 33 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.24 (s, 6H), 3.37 (s, 2H), 4.34 (dd, 1H), 4.65 (dd, 1H), 4.77 (dd, 1H), 5.10 (m, 2H), 6.74 (d, 2H), 7.24 (m, 2H), 7.55 (m, 3H), 8.15 (d, 2H), MS (APCI+) m/z 379 [M+H]+, LC purity: 95%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([Sn](C)(C)C)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.Br[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: Brc1ccncc1
Reactant: CSc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
2-Methylthio-4-[5-trimethylstannyl-benzimidazol-1-yl]pyrimidine (150 mg), 4-bromopyridine (180 mg), tri-o-tolylphosphine (5 mg) and tris(dibenzylidineacetone)dipalladium(0) (7.5 mg) were dissolved in DMF (3 mL) and heated to 100° C. for 1 hour. Upon cooling to rn and evaporation of solvent, the reaction residue was directly purified by column chromatography (SiO2,5% MeOH in CH2Cl2) to yield 100 mg of the title compound. Mass spectrum (ESI) 320.2 (M+1).
Reaction SMILES: CO[CH2:3][N:4]([CH2:20][Si](C)(C)C)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[CH:25]([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[N:31]=1)=[CH2:26].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>ClCCl.C(O)(C(F)(F)F)=O.CC(C)=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:32][C:30]1[N:31]=[C:27]([CH:25]2[CH2:26][CH2:20][N:4]([CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH2:3]2)[S:28][CH:29]=1
Reactant: C=Cc1nc(C)cs1
Reactant: COCN(CCc1ccccc1N1CCCCC1=O)C[Si](C)(C)C
Agent: O=C(O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1csc(C2CCN(CCc3ccccc3N3CCCCC3=O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
At 0° C., 1-[2-(2-{(methoxymethyl)[(trimethylsilyl)methyl]amino}ethyl)phenyl]piperidin-2-one a5-2 (696 mg, 2 mmol, 2 eq) is slowly added to 2-ethenyl-4-methyl-1,3-thiazole a5-3 (125 mg, 1 mmol, 1 eq) diluted in dichloromethane/TFA (90 μl/10 μl). The mixture is stirred at room temperature overnight. Solvent is removed under reduced pressure and the residue is purified by basic reverse phase chromatography on silicagel (gradient: acetonitrile/H2O/NH4OH from 30/70/0.1 to 60/40/0.1 in 10 minutes). The product is dissolved in a minimum of acetone and oxalic acid (1 eq) is added to form the salt that is filtered, washed with diethyl ether and dried under vacuum to afford 215 mg of 1-(2-{2-[3-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one oxalate 87.
Reaction SMILES: C([C:3]1[C:10]([CH2:11][N:12]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[N:31]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH2:32][CH2:33][CH3:34])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=2)=[CH:9][C:8]([C:39]([F:42])([F:41])[F:40])=[CH:7][C:4]=1[C:5]#[N:6])C.Br[CH2:44][CH2:45][CH2:46][C:47]([O-:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].[C:56](OCC)(=O)[CH3:57]>CN(C)C=O>[C:5]([C:4]1[CH:3]=[C:10]([CH:9]=[C:8]([C:39]([F:41])([F:40])[F:42])[CH:7]=1)[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:35][CH:36]1[CH2:37][CH2:38]1)[CH2:32][CH2:33][CH3:34])[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:56][CH3:57])=[O:48])=[CH:15][N:14]=1)#[N:6]
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C#N)c1CC)c1ncc(O)cn1
Reactant: CCOC(C)=O
Reactant: O=C([O-])CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-{[[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (250 mg) and 4-bromobutyrate (76.9 μl) is dissolved in N,N-dimethylformamide (3.7 ml) and thereto is added potassium carbonate (74 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=8:1) to give ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (220 mg). MS (m/z): 678 [M+H]+
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH3:17]CCCC.C(OCC)C>>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]2[O:7][CH2:17]2)[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: CCCCC
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOCC
Product: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1

Procedure:
Following General Procedure EC and using 3,5-bis-(trifluoromethyl)benzaldehyde (Lancaster), the title compound was isolated after flash chromatography with 10:1 pentane/diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][C:41]([NH:43][C:44]([CH3:51])([CH3:50])[C:45]([O:47][CH2:48]Cl)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C:36]([O:40][C:41]([NH:43][C:44]([CH3:51])([CH3:50])[C:45]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)NC(=O)OC(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in DMF (2.5 mL), KOH (69 mg, 0.4 mmol), and a solution of chloromethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (158 mg, 0.61 mmol) in DMF (0.5 mL). The title compound was purified by a silica gel columnchromatography (PE/EtOAc (v/v)=4/1 to 3/1) and was obtained as a white solid (339 mg, 78.7%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:42])=[O:26]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1ccccc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of alcohol 3 (342 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipecolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-(3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (470 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.50-6.90 (m, 9 H), 5.93 (t, J=6.0 Hz, 1 H), 5.46 (d, J=3.4 Hz, 0.83 H, pipercolate α-H of rotamer A), 4.67 (s, 2 H), 3.50 (d, J=12.9 Hz, 1 H), 3.32 (td, J=12.5, 3.0 Hz, 1 H), 2.75 (m, 2 H), 2.53 (d, J=13.6 Hz, 1 H), 2.41 (m, 1 H), 2.22 (m, 1 H), 2.97-2.71 (m, 6 H), 1.62 (s, 9 H), 1.38 (s, 3 H), 1.35 (s, 3 H), 1.03 (t, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.3, 175.0, 170.0, 168.0, 167.5, 158.5, 141.7, 141.2, 130.2, 128.9, 128.7, 126.5, 120.2, 114.7, 113.6, 82.8, 66.1, 51.6, 47.1, 44.5, 38.2, 32.9, 32.0, 28.4, 26.8, 25.3, 24.0, 23.4, 21.6, 9.2. HRMS(FAB): (M+Na)+ calcd: 602.3094, found: 602.3090.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:9]([O:19][N:20]=C(C)C)=[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]3=[N:12][CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.C(O)C.O>CCOCC>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:8]3[C:9](=[C:10]4[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]4=[N:12][CH:13]=3)[O:19][N:20]=2)=[CH:4][CH:3]=1
Reactant: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccc(Cl)cc3)cnc21
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCn1ncc2c3onc(-c4ccc(Cl)cc4)c3cnc21
Yield: 43.9 %

Procedure:
5-(4-chlorobenzoyl)-1-ethyl-4-isopropylideneaminooxy-1H-pyrazolo-[3,4-b]pyridine (3.54 g) was refluxed for 2 hours in 75 ml of 2:1 5% hydrochloric acid/ethanol. The reaction mixture was distributed between water and ether and then the ether layer was washed with 5% sodium hydroxide. Evaporation of the ether gave 1.30 g of product. An analytical sample was recrystallized from hexane which had mp 195°-197° C.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[F:11][C:12]1[CH:13]=[C:14]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
To a solution of 0.704 g (5.67 mmol) of orcinol monohydrate and 1.00 g (5.15 mmol) of 3-fluorobenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture was stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.41 g of a pale amber-colored oil. This material was flash chromatographed on 65 g of silica gel with 3% ethyl acetate-dichloromethane to afford 935 mg (68%) of the desired product as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 7.66 (ddd, 1H, J=7.8, 1.7, 1.1 Hz), 7.55 (m, 2H), 7.38 (tdd, 1H, J=8.3, 2.6, 1.1 Hz), 6.56 (m, 1H), 6.40 (m, 1H), 6.33 (td, 1H, J=2.2, 0.5 Hz), 5.29 (s, 1H) and 2.23 (s, 3H).
Reaction SMILES: C(N1C2C(=CC=CC=2)C=C1)(C)C.[CH:13]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](=[O:29])[C:26]([Cl:28])=[O:27])=[CH:17]1)([CH3:15])[CH3:14].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:28].[OH:41][CH2:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][NH:30][C:26](=[O:27])[C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=2)=[O:29])[CH2:34][CH2:35]1.[OH:41][CH2:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][NH:30][C:26](=[O:27])[C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=2)=[O:29])[CH2:34][CH2:35]1
Reactant: NCCN1CCC(CCO)CC1
Reactant: CC(C)n1cc(C(=O)C(=O)Cl)c2ccccc21
Agent: CC(C)n1ccc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1cc(C(=O)C(=O)NCCN2CCC(CCO)CC2)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared according to general procedure B described in Scheme 1. N-Isopropylindole (150 mg, 0.94 mmol) was converted to 2-(1-isopropyl-1H-indol-3-yl)-2-oxoacetyl chloride as described in example 1 and treated with a solution of 2-(1-(2-aminoethyl)piperidin-4-yl)ethanol (236 mg, 1.13 mmol), triethylamine (1.3 mL, 9.4 mmol) in DCM (2 mL) and stirred at RT for 14 h. The reaction mixture was then washed with sat. NaHCO3 (1×3 mL), H2O (1×3 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica chromatography (Biotage, 10-50% MeOH/DCM, 30 min.) to provide N-(2-(4-(2-hydroxyethyl)piperidin-1-yl)ethyl)-2-(1-isopropyl-1H-indol-3-yl)-2-oxoacetamide and further purified using reverse phase HPLC. The purified material was converted to the HCl salt to afford (27 mg, 7% yield): 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 8.45 (m, 1H), 7.93 (t, 1H), 7.44 (m, 1H), 7.34 (m, 2H), 4.71 (m, 1H), 3.71 (t, 2H), 3.47 (q, 2H), 2.92 (d, 2H) 2.55 (t, 2H), 2.01 (t, 2H), 1.70 (d, 2H), 1.62 (d, 6H), 1.53 (q, 3H), 1.33 (t, 3H); MS (ESI) m/z: Calculated for C22H31N3O3: 385.2. Found: 385.5 (M+H)+.
Reaction SMILES: C([Si](C)(C)O[C:7]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:8]=1)(C)(C)C.C1C[O:27]CC1>>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C:9]1[C:8](=[O:27])[CH2:7][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1ccccc1C=C1C=C(O[Si](C)(C)C(C)(C)C)CCCC1
Product: Cc1ccccc1CC1=CCCCCC1=O
Reaction time: 0.5 h

Procedure:
A solution of n-tetra-n-butylammonium fluoride (1M) in THF (1.35 mmol) is added using a syringe to a solution of the compound obtained in Step A (1.34 mmol) in 15 ml of anhydrous THF at 0° C., and the whole is stirred at that temperature for 1 hour 30 minutes. The reaction mixture is then concentrated to dryness and deposited directly over a column of silica gel (heptane/AcOEt 9/1) to yield the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23]1.C(N(CC)CC)C.C([O-])(=O)C>C(#N)C>[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:33])[C:18](=[O:20])[CH2:17][O:16][C:12]3[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=3)[CH2:28][CH2:27]2)[CH2:23][CH2:24]1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(CC2CC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Compound 9 (100 mg), 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine (56.6 mg) and triethylamine (234 μL) were suspended in acetonitrile (2 mL). While the suspension was cooled with ice, a 50% propane phosphonic acid anhydride ethyl, acetate solution (273 mg) was added portionwise. The equipment used to add the 50% propane phosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (0.5 mL) and was stirred at room temperature (20 to 30° C.) overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=30:1) to give 79 mg (52% yield) of the desired product as a pale yellow amorphous.