Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.CN(C)C=O.[H-].[Na+].Br[CH:31]([CH2:37][CH3:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O.C(OCC)(=O)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:31]([CH2:37][CH3:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: CCOC(=O)C(Br)CC
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 0.25 h
Yield: 111.6 %

Procedure:
To a 0° C. solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 0.0063 mol) in N,N-dimethylformamide (40 mL, 0.5 mol) was added sodium hydride (0.30 g, 0.0076 mol). After 15 minutes, ethyl 2-bromobutyrate (1.4 mL, 0.0095 mol) was added. After 4.5 hours, ethyl acetate and water were added. The organic phase was washed with water twice and saturated NaCl. The organic phase was then and the solvent was removed by rotary evaporation to give 3.02 g of a thick orange oil (110% yield). 1H NMR (400 MHz, CDCl3): δ 8.92 (1H, s); 8.49 (1H, s); 8.35 (1H, s); 7.45 (1H, d); 6.85 (1H, d); 6.75 (2H, s); 5.0 (1H, t); 4.35 (2H, m); 3.6 (2H, t); 2.35 (2H, m); 1.35 (6H, m); (1.0 (3H, m); 0 (9H, s). LCMS (M+1): 430.
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][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][Br:37])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:45]([OH:53])(=[O:52])[CH:46]([CH2:48][C:49]([OH:51])=[O:50])[OH:47].[H][H]>O1CCCC1.[Pd].CCOCC>[Br: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][CH2:23][CH2:22][CH2:21][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:52][C:45](=[O:53])[CH:46]([CH2:48][C:49]([OH:51])=[O:50])[OH:47])=[O:17])=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC(O)C(=O)OC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
To a warm solution of N-carbobenzyloxy-4-(16-bromohexadecylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetic acid to yield the title compound as a tan, crystalline mass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH3:10].[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](O)=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:15]1[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[N:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]=1[CH3:10]
Reactant: CCC(=O)c1ccccc1F
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl

Procedure:
Prepared according to Procedure J using 1-(2-fluorophenyl)propan-1-one and 2-amino-6-fluorobenzoic acid in phosphorous oxychloride to afford a colorless solid upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=290.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:33]([C:36]2[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1>CN1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Reactant: C1CCNC1
Agent: CN1CCCC1
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)cc1)C2
Temperature: 100 °C
Reaction time: 72 h
Yield: 52.9 %

Procedure:
A solution of pyrrolidine (0.046 mL, 0.557 mmol) and (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (0.1 g, 0.186 mmol) in N-methylpyrrolidine (2 mL) was stirred at 50° C. in a sealed vial for 6 hours, then allowed to stand at room temperature for 72 hours. The reaction mixture was then stirred at 100° C. for an additional 5 hours, cooled to room temperature, and purified directly by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 50-70% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a pale yellow solid (58 mg). LCMS (Method F, ES-API): RT 2.81 min, m+H=590.0; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.1 Hz), 7.62 (d, 1H, J=3.1 Hz), 7.54-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.28 (s, 1H), 7.219-7.12 (m, 2H), 6.50-6.45 (m, 3H), 5.46 (dd, 1H, J=12.1, 2.0 Hz), 4.21 (d, 1H, J=16.8 Hz), 3.86-3.80 (m, 1H), 3.35-3.30 (m, 4H), 2.92-2.81 (m, 2H), 2.64 (d, 1H, J=12.2 Hz), 2.52-2.36 (m, 2H), 2.07-2.01 (m, 4H).
Reaction SMILES: C(OC([N:8]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH2:31]Br)[C:9]1=[O:40])=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49]>C(#N)C>[Cl:39][C:36]1[CH:37]=[C:38]2[NH:8][C:9](=[O:40])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][C@@H:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH2:31][N:54]3[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]3)[C:33]2=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cc(F)ccc1CBr
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccc(F)cc2[C@H]2NC(=O)C[C@@H](c3cccc(Cl)c3)[C@]23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-(2-bromomethyl-5-fluoro-phenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo-spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (30 mg, 0.046 mmol) prepared in example 164b in acetonitrile (5 mL) was added K2CO3 (13 mg, 0.094 mmol) and 1-methanesulfonyl-piperazine (15 mg, 0.094 mmol). The mixture was refluxed for 2 h, concentrated. The residue was dissolved in trifluoroacetic acid and stirred at room temperature for 30 min, then concentrated and purified by prep-HPLC to give (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-fluoro-2-(4-methanesulfonyl-piperazin-1-yl)methyl-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as solid (5 mg, 17%).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To 77 mM solution of tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (1.3 mL) in toluene and absolute ethanol (2:1) was added o-tolylboronic acid (0.0136 g, 0.1 mmol) followed by 1M solution of cesium carbonate (0.6 mL) and 1,1-bis(Di-tBuppf)PdCl2 (0.005 g). The reaction mixture was shaken at 110° C. for 24 hours. On completion of the reaction, the reaction mixture was extracted with EtOAc (2×2 mL). The organic layers were combined and concentrated under reduced pressure to give the desired crude product, tert-butyl 1-o-tolyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate as an brown solid, which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]2.[C:19]([S:22][CH2:23][CH:24]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[C:25](Cl)=[O:26])(=[O:21])[CH3:20].O>CC(N(C)C)=O>[C:19]([S:22][CH2:23][CH:24]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[C:25]([N:14]([CH:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH2:6][CH2:7]1)[CH2:15][C:16]([OH:18])=[O:17])=[O:26])(=[O:21])[CH3:20]
Reactant: COc1cc2c(cc1OC)C(NCC(=O)O)CC2
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1OC)C(N(CC(=O)O)C(=O)C(CSC(C)=O)CSC(C)=O)CC2
Temperature: 25 °C
Yield: 45.5 %

Procedure:
N-(5,6-Dimethoxy-1-indanyl)glycine (4.0 g) is suspended in 40 ml of dimethylacetamide, then 4.4 g of 3-acetylthio-2-acetylthiomethylpropionyl chloride is added dropwise with stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 400 ml of water and extracted with 300 ml of ethyl acetate. The extract is washed with 30 ml of 10% hydrochloric acid and with water, and dried. After ethyl acetate is distilled off under reduced pressure, ethyl ether is added to the residue and the mixture is allowed to stand at room temperature. The resulting crystalline precipitates are collected by filtration to give 3.4 g of N-(3-acetylthio-2-acetylthiomethylpropionyl)-N-(5,6-dimethoxy-1-indanyl)glycine as colorless needles melting at 140°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[CH2:16][CH:17]=[CH2:18])[C:10]2=[O:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>COCCOC.C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=4)=[CH:21][CH:20]=3)[CH2:16][CH:17]=[CH2:18])[C:10]2=[O:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(I)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cs+]
Agent: [F-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(-c2cccc(C#N)c2)cc1
Yield: 49 %

Procedure:
A solution of 1-(3,5-dichloro-phenyl)-3-[2-(4-iodo-phenyl)-pent-4-enyl]-imidazolidin-2-one (0.128 g, 0.255 mmol), 3-cyanophenyl boronic acid (0.113 g, 0.766 mmol, 3 eq), tris(dibenzylidene-acetone)-dipalladium(O) (0.025g, 0.0255 mmol, 10 mol %), triphenylarsine (0.031 g, 0.1 mmol, 40 mol %) and cesium fluoride (0.075 g, 0.51 mmol, 2 eq) in DME (13 mL) and ethanol (3 mL) was microwaved at 50W for 7 h and then at 100W for 1 h. The mixture was diluted with EtOAc (50 mL), filtered through a pad of celite 545® and the filtrate washed with saturated aqueous Na2CO3 solution (25 mL). The aqueous layer was extracted twice with EtOAc (50 mL). The combined organic extracts were washed with saturated aqueous Na2CO3 solution (25 mL) and saturated aqueous sodium chloride solution (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a dark oil. Purification by flash column chromatography eluting 15–20% EtOAc/hexanes gave 4′-{1-[3-(3,5-dichloro-phenyl)-2-oxo-imidazolidin-1-ylmethyl]-but-3-enyl}-biphenyl-3-carbonitrile (0.059 g, 0.125 mmol, 49%) as a dark foam. 1H NMR (300 MHz, CDCl3): δ 7.98 (m, 1H), 7.92 (m, 1H), 7.74 (m, 1H), 7.64 (m, 3H), 7.58 (d, 2H), 7.45 (d, 2H), 7.11 (dd, 1H), 5.80 (m, 1H), 5.12 (m, 2H), 3.75 (m, 3H), 3.55 (m, 1H), 4.42 (m, 1H), 3.26 (m, 2H), 2.58 (dd, 2H).
Reaction SMILES: [C:1]12C(=CC=CC=1)NC(=O)OC2=O.[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](=C)=[N-]>CCOCC>[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH3:1])=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21

Procedure:
Following the procedure set forth in Preparation A, steps (2-3), isatoic anhydride was converted to 1-heptyl-4-hydroxy-3-ethoxycarbonyl-2(1H)-quinolinone, which upon reaction with excess diazomethane in ether gave the title compound. That the expected product was obtained was confirmed by the spectral data: MS: m/e 345 (M.+).
Reaction SMILES: C[Mg]Cl.[CH2:4]([O:11][C@@H:12]([CH3:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([OH:32])[CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+].[CH2:36](OCC)C>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:4]([O:11][C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([OH:32])[CH2:20][CH3:36])[CH3:33])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CCCCCC[C@H](C)OCc2ccccc2)cc1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@H](O)CCCCCC[C@H](C)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To 11.8 ml of a commercially available solution of 20% methyl magnesium chloride (31.4 mmol) in tetrahydrofuran were added 20 ml abs. tetrahydrofuran. The solution was cooled to −78° C., and 595 mg (3.14 mmol) copper-I-iodide were added. After stirring for 15 min, a solution of 4.55 g (10.5 mmol) (2R,9S)-9-benzyloxy-1(p-tolylsulfonyloxy)-decane-2-ol in 10 ml abs. tetrahydrofuran was added over a period of 2 h. The solution was warmed to −30° C. and stirred for another hour. Subsequently, 150 ml saturated aqueous ammonium chloride and 50 ml diethyl ether were added at 0° C. The aqueous layer was extracted three times with 150 ml ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated in vacuo. Flash chromatography (16% ethyl acetate in hexane) furnished 2.6 g (9.4 mmol, 90%) (2S,9S)-2-benzyloxyundecane-9-ol
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:43](O)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.C(NCC(NC[C@]1(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)=O)(=O)C>CN(C=O)C>[CH:29]1[C:30]2[CH:31]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:43]([NH:1][CH2:2][C@:3]3([CH2:18][OH:19])[O:7][C@@H:6]([N:8]4[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]4=[O:10])[CH2:5][C@@H:4]3[OH:17])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[C:32]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Agent: CC(=O)NCC(=O)NC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)[C@H](CC(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O

Procedure:
4′-C-(Aminomethyl)thymidine (4) (0.025 g, 0.1 mmol), N-(9-fluorenylmethyloxycarbonyl)leucine (0.071 g, 0.2 mmol), TSTU (0.09 g, 0.3 mmol) and diisopropylethylamine (0.065 g, 0.5 mmol, 0.087 mL) were combined in DMF (1 mL) according to the procedure used to prepare compound (19). The title compound (20) was obtained as an amorphous solid (0.056 g). δH(300 MHz, CD3OD) 7.86–7.37(8H, m, Fmoc), 7.74(1H, s, H-6), 6.24(1H, dd, H-1′), 4.56(1H, dd, H-3′), 3.68(2H, 2d, H-5′), 3.40(2H, 2d, 4′-C—CH2), 2.37(2H, m, H-2′), 1.70(3H, m, leucyl CH, CH2), 1.66(3H, s, 5-CH3), 1.05(3H, d, leucyl CH3), 1.02(3H, d, leucyl CH3); ES +ve m/z 607(M+H)+, 629(M+Na)+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH3:15]O>>[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: CO
Reactant: N[C@@H]1CCC[C@H](C(=O)O)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCC[C@@H](N)C1
Yield: 90.9 %

Procedure:
Thionyl chloride (0.6 ml) was added to solution of cis-3-amino-cyclohexanecarboxylic acid (bought from AMRI, USA, cat.-no.: A00342, 0.50 g, 2.80 mmol) in MeOH (20 ml) at 0° C. and stirred at reflux for 12 h. The volatiles were evaporated in vacuo and the resulting residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford 400 mg (90.9%) of cis-methyl 3-aminocyclohexanecarboxylate as colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[N:7]([O-])=O.[Na+].C(ON=O)C[CH:13]([CH3:15])C>>[N:1]1[C:2]2=[CH:6][CH:5]=[N:4][N:3]2[CH:15]=[CH:13][N:7]=1
Reactant: CC(C)CCON=O
Reactant: O=N[O-]
Reactant: Nc1cc[nH]n1
Agent: [Na+]
Product: c1cn2nccc2nn1

Procedure:
The method of Ege and Gilbert, J. Het. Chem. 1981, 18, 675-677, is used to prepare the desired ring system (Scheme 4). Thus, aminopyrazole 4-A is converted to diazonium salt 4-B, using sodium nitrite/acid or such reagents as isoamylnitrite. The diazonium salt is condensed with a phosphorus ylide compound 4-C to give the pyrazolo[5,1-c] [1,2,4]triazine product.
Reaction SMILES: [OH:1][C@H:2]([C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CC#N>[C:27]([CH2:26][O:1][C@@H:2]([C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1)#[N:28]
Reactant: N#CCBr
Reactant: Cc1cccc([C@@H](O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc([C@H](OCC#N)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-((S)-hydroxy(m-tolyl)methyl)piperidine-1-carboxylate (30.5 g, 0.1 mol) in MeCN (300 mL), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 hr at rt. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added in portions. The mixture was stirred for 0.5 hr at −20° C. continually. The reaction was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated. Crude (R)-tert-butyl 3-((R)-(cyanomethoxy)(m-tolyl)methyl)piperidine-1-carboxylate was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[C:21]2[C:16](=[CH:17]C=CC=2)[CH:15]=[CH:14]1.[H-].[Na+].S([O-])(=O)(=O)C.C[N:30](C=O)C>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:15][C:16]2[CH:21]=[N:13][CH:14]=[N:30][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Reactant: c1ccc2[nH]ccc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2ccn(Cc3cncnc3)c2c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
6-Nitroindole-1H-indole (35.6 g, 220 mmol) was dissolved in 750 mL of DMF and NaH (50%, 12 g, 250 mmol) was added in portions and the mixture was stirred for 1 hour. The mixture was cooled to −40° C. and the solution of the mesylate was added dropwise. The mixture was allowed to reach room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water (2×) and brine and dried over Na2SO4. After concentration in vacuo the material was purified by means of column chromatography (silica, heptane/ethyl acetate (1:1)→(1:4)) affording compound the title compound as a yellow solid (14 g, 55 mmol, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc2cn[nH]c2c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg, 1.01 mmol) in DMF (5 mL) was added cesium carbonate (494 mg, 1.515 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (215 mg, 1.515 mmol) was added. The reaction solution was stirred for 2 h and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give crude product which was purified by chromatographic column to afford the desired product 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine. LCMS-ESI+: calc'd for C7H6BrN3: 211.98 (M+H+); Found: 212.1 (M+H+).