Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH2:15][C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:18]([C:21]1[S:22][C:23]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:24]([CH3:26])[N:25]=1)=[N+:19]=[N-:20]>>[CH2:30]([NH:29][C:27]([C:23]1[S:22][C:21]([N:18]2[CH:17]=[C:16]([CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:20]=[N:19]2)=[N:25][C:24]=1[CH3:26])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(Cc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 69 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 3-phenyl-1-propyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 69% yield: mp 139-141° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.35-7.28 (m, 10H), 6.29 (br s, 1H), 4.60 (t, J=6.0 Hz, 2H), 4.13 (s, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.5, 153.2, 149.1, 137.9, 137.5, 128.9, 128.8, 128.7, 127.8, 126.8, 124.1, 119.2, 44.3, 32.1, 17.3; MS (ES+) m/z 390.2 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.FC(F)(F)C(O[C:38]1[C:43]([F:44])=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48])=O.Cl>C(Cl)Cl>[F:44][C:43]1[C:38]([O:12][C:11]([C:8]2[N:9]=[N:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:7]=2)=[O:13])=[C:39]([F:48])[C:40]([F:47])=[C:41]([F:46])[C:42]=1[F:45]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CCCCc1nnc(C(=O)O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of the carboxylic acid (24.4 mmol, 8.6 g) in DCM (100 mL) was added pyridine (81 mmol, 6.4 g) followed pentafluorophenyl trifluoroacetate (40.52 mmol, 11.3 g) drop-wise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 8 h. The reaction was added to 1N HCl (100 mL), and the product was extracted with ethyl acetate. The crude product was purified using a mixture of hexanes in ethyl acetate on a 330 g silica gel ISCO column to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (9.0 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH:28]5[CH2:29][CH2:30][CH:24]4[CH2:25][N:26]([CH3:31])[CH2:27]5)=[O:22])=[CH:18][C:17]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>ClCCCl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([OH:40])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH:28]5[CH2:29][CH2:30][CH:24]4[CH2:25][N:26]([CH3:31])[CH2:27]5)=[O:22])=[CH:18][C:17]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
tert-Butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (300 mg, 0.504 mmol) was dissolved into DCE (5 mL) and then TFA (700 μl, 9.09 mmol) was added (reaction became green) and the reaction was stirred at rt for 1 h (˜70% conversion by LCMS). More TFA (700 μl, 9.09 mmol) was added and the reaction was stirred 1 h (complete by LCMS). The reaction mixture was concentrated on a rotary evaporator, diluted with diethyl ether and reconcentrated twice to yield 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid trifluoroacetate (362 mg, 0.55 mmol, quant.) as a dark yellow solid. Used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-2.13 (m, 21H), 2.68-2.86 (m, 1H), 3.36-3.50 (m, 2H), 3.90 (s, 3H), 4.11-5.35 (m, 2H), 7.14 (s, 1H), 7.18-7.28 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.21 (br s, 1H), 9.55 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC-MS retention time: 2.50 min; 538 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 65 °C

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (20.0 g), anhydrous potassium carbonate (26.2 g) and 2-bromopropane (18.3 mL) in dry dimethylformamide (300 mL) is stirred and heated at 5514 65° C. for 24 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo at 40° C., to give 4-methoxy-3-prop-2-yloxybenzaldehyde, in the form of an oil (24.2 g).
Reaction SMILES: CO/C(/C)=C\C(Cl)=O.S1C2C=CC=CC=2N=C1S[S:19][CH:20]1[N:23](/[C:24](=[C:28](\[O:30][CH3:31])/[CH3:29])/[C:25](Cl)=[O:26])[C:22](=[O:32])[CH:21]1[NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.[C:51]([OH:55])([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl>[C:51]([O:55][C:25]([CH:24]1[N:23]2[C:22](=[O:32])[C@@H:21]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:20]2[S:19][CH:29]=[C:28]1[O:30][CH3:31])=[O:26])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)O
Reactant: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Agent: CO/C(C)=C\C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2-[4-benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is added dropwise over the course of 15 minutes at 0° C., whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of methylene chloride. After a further 15 minutes stirring, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. IR spectrum (in CH2Cl2): characteristic bands at 5.60, 5.77, 5.90 and 8.29μ.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][CH2:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[NH:33][C:32](=[O:34])[C:31]3[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=3[O:35][CH3:36])[N:25]=2)=[CH:19][C:18]=1[CH3:39].O>CN(C)C=O>[CH3:36][O:35][C:30]1[CH:29]=[C:28]([O:37][CH3:38])[CH:27]=[C:26]2[C:31]=1[C:32](=[O:34])[NH:33][C:24]([C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][CH2:15][CH2:14][N:6]3[C:7](=[O:9])[CH2:8][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:10])=[C:18]([CH3:39])[CH:19]=1)=[N:25]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: CC(C)N1CC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)CN(C(C)C)C4=O)c(C)c3)nc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 1-isopropyl-imidazolidine-2,4-dione (0.10 g, 0.70 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 31 mg, 0.77 mmol) and the reaction mixture was stirred for 10 minutes. Then, 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.32 g, 0.73 mmol) was added. The reaction mixture was stirred at 55° C. for 16 hours, then poured into water (100 mL). The solid was filtered and dried. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) to give the title compound as a white solid. Yield: 0.09 g (26.0%). MP 219-221° C. 1H NMR (400 MHz, DMSO): δ 9.64 (s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.42 (m, 1H), 4.02 (m, 2H), 3.98 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 2H), 2.32 (s, 6H) 1.22 (d, J=6.4 Hz, 6H). MS (ES+) m/z: 495.16 (M+1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(S)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCc2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of trans-N-cyanomethyl-2-(4-methylsulfanylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.1 g, 0.298 mmol), phenethyl mercaptan (0.103 mL, 0.764 mmol) and cesium carbonate (0.25 g, 0.764 mmol) was dissolved in dimethylformamide (1.5 mL) and heated at 100° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, evaporated to dryness, and purified on a short plug of silica gel (2040% ethyl acetate/CHCl3), yielding the desired product. NMR (DMSO-d6): 1.1 (3H, m); 1.3 (1H, m) 1.6-1.7 (3H, m); 2.03 (2H, m); 2.16 (1H, d): 2.92 (3H, m); 3.15 (1H, dd); 3.36 (2H, m); 4.03 (2H, d); 7.1 (1H, d); 7.25 (4H, m); 7.47 (2H, d); 7.68 (2H, d); 8.56 (1H, t). MS [ESI, (M+Na)+] m/z=479 amu.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:29])/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21](/[C:15](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: NCCCCc1cccnc1
Reactant: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCCCC/C(=C/C=C/C(=O)NCCCCc1cccnc1)c1ccc(OC)cc1
Yield: 70.5 %

Procedure:
As in Example 134, a solution of (2E,4Z)-5-(4-methoxypenyl)-2,4-decadienoic acid 4-nitrophenyl ester (2 g) and 3-pyridinebutanamine (0.9 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. After the usual work up, the crude product was purified by HPLC (ethyl acetate) and the resulting solid was triturated with ether to give 1.45 g of (2E,4Z)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-decadienamide. A portion was recrystallized from ethyl acetatehexane to furnish the analytical sample, mp 81.5°-82.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][C:21]([CH3:23])=[CH2:22])=[C:4]([Cl:9])[CH:3]=1
Reactant: C=C(C)CCOP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccc(Br)cc1Cl
Temperature: 85 °C

Procedure:
To a mixture of 4-bromo-2-chlorophenol (0.98 g, 4.71 mmol), and Cs2CO3 (2.05 g, 6.28 mmol) in DMF (4.49 mL) at room temperature was added 3-methylbut-3-en-1-yl diphenyl phosphate (1.00 g, 3.14 mmol, synthesized according to a procedure in U.S. Pat. No. 5,006,550, 9 Apr. 1991) dropwise via a syringe. The reaction mixture was heated to 85° C. for 1 hour. It was then allowed to cool to room temperature and was diluted with water (20.0 mL). The resulting mixture was extracted with hexane (75.0 mL, 2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([S:24]([OH:27])(=O)=[O:25])=[N:7]1.[CH3:32][N:33](C=O)[CH3:34].S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([S:24]([N:33]([CH3:34])[CH3:32])(=[O:25])=[O:27])=[N:7]1
Reactant: CN(C)C=O
Reactant: COc1c2n(c3c(S(=O)(=O)O)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: COc1c2n(c3c(S(=O)(=O)N(C)C)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-sulfonic acid (32 mg, 68 μmol), anhydrous DMF (11 μL, 0.14 mmol), and thionyl chloride (1.05 g, 8.84 mmol) in anhydrous acetonitrile (0.6 mL) was heated at 80° C. for 30 minutes. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous acetonitrile (3 mL) and treated with a solution of dimethylamine in THF (1 mL, 2 M). The mixture was stirred at room temperature for one hour and treated with aqueous sodium hydroxide (0.5 mL, 1 M). After stirring at room temperature for one hour, the product mixture was concentrated under vacuum. The residue was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=O)[CH:26](Br)[CH2:27]C)C.COCCCC.C[O-].[Na+]>O.C(O)(=O)C>[CH2:26]([C:25]([CH2:15][C:14]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:24])[CH3:27]
Reactant: COc1ccc(C=O)cc1OCCOCc1ccccc1
Reactant: CCOC(=O)C(Br)CC
Agent: CCCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)Cc1ccc(OC)c(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
24 g of the product of step (ii) 21.5 g bromobutyric acid ethyl ester and 30 ml t.butyl methyl ether are added dropwise over 50 mins. at 5° C. to a pre-prepared suspension of sodium methylate in 25 ml t.butyl methyl ether. The reaction mixture is stirred for 45 mins. at ca. 5° C. and then stirred for 12 hrs. at room temperature. The pH is adjusted to 5 by addition of glacial acetic acid and the obtained suspension diluted with H2O and extracted 3× with t.butyl methyl ether. The organic phase is extracted with NaHCO3 (1×) and brine (1×), and evaporated to ca. 100 ml. 13.5 ml 50% aqueous NaOH are added drop-wise and the whole stirred for 2 hrs. at 40° C., diluted with 50 ml. H2O and stirred for a further 30 mins. at room temperature. The organic phase is separated and the aqueous phase adjusted to pH 1 at max. 40° C. with 15 ml conc. HCl. The reaction mixture is stirred at 40° C. for a further 1.5 hrs., cooled to room temperature and extracted with toluene. The organic phase is washed with NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to yield the title compound as an oil.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([O-:16])=[O:15].[F-].[K+].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[S:6][C:5]([C:7]3([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: OC1(c2ncc(I)s2)CCOCC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)cc1
Temperature: 90 °C

Procedure:
A solution of Example 1B (1.0 g, 3.2 mmol), 4-nitrophenylboronic acid (0.75 g, 4.5 mmol), KF (0.56 g, 9.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.22 g, 0.32 mmol) in a solvent mixture of dimethoxyethane (5 mL) and methanol (5 mL) was heated to 90° C. for 16 h. The reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and H2O (10 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×10 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 307 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.O.[F:13][C:14]([F:27])([F:26])[C:15]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH2:17].C(=O)(O)[O-].[Na+]>C(OCC)C>[F:13][C:14]([F:26])([F:27])[C:15]([C:18]([F:21])([F:20])[F:19])([C:22]([F:23])([F:24])[F:25])[CH:16]1[O:9][CH2:17]1
Reactant: C=CC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)C(C1CO1)(C(F)(F)F)C(F)(F)F

Procedure:
32.9 g (105 mmol) of 3-chloroperbenzoic acid with a peracid content of 55% is added in portions with stirring and cooling with water to a solution of 24.6 g (100 mmol) of 4,4,4-trifluoro-3,3-bis(trifluoromethyl)-but-1-ene in 150 ml of absolute diethyl ether. After addition is completed, it is refluxed for 3 hours. It is allowed to cool, and the solution is stirred in cold, saturated sodium bicarbonate solution. The ethereal solution is separated, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation on a column. The residue is purified by bulb tube distillation (vacuum 30 mbar, 130° C. bath).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH2:8][C:9](=[O:11])[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Solvent: CCO
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1OC
Yield: 21.5 %

Procedure:
Using General Procedure A; ethyl 3,4-dimethoxybenzoylacetate (3.00 g, 11.9 mmol, 1.1 equ.) in ethanol (60 mL) was treated at 0° C. with phenylhydrazine (1.17 mL, 10.8 mmol, 1.0 equ.) to afford 3-(3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (920 mg, 2.32 mmol, 22%) after purification by crystallization (ethanol) as a yellow powder. 1H-NMR (400 MHz) CDCl3: 8.00-7.97 (d, 1H), 7.48-7.42 (m, 3H), 7.25-7.21 (t, 1H), 7.17-7.14 (dd, 1 H), 6.91-6.89 (d, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.83 (s, 2H), 13C-NMR (100 MHz) CDCl3: 170.1, 154.4, 151.4, 149.4, 138.1, 128.8, 125.2, 123.8, 120.1, 119.1, 110.7, 107.6, 56.0, 56.0, 39.7; LC/MS-MS: 297.0→218.2 m/z; GS1 and GS2 at 30, DP=96, CE=37, CXP=18, tR=3.98 min.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[CH3:10][C:11]1([CH3:32])[O:15][C@@H:14]2[C@@H:16]([CH2:29][NH:30][CH3:31])[O:17][C@@H:18]([N:19]3[CH:27]=[N:26][C:25]4[C:20]3=[N:21][CH:22]=[N:23][C:24]=4[NH2:28])[C@@H:13]2[O:12]1.[BH3-]C#N.[Na+]>CO>[CH3:9][O:8][C:6]([CH:4]1[CH2:5][CH:2]([N:30]([CH2:29][C@@H:16]2[C@@H:14]3[C@@H:13]([O:12][C:11]([CH3:32])([CH3:10])[O:15]3)[C@H:18]([N:19]3[CH:27]=[N:26][C:25]4[C:20]3=[N:21][CH:22]=[N:23][C:24]=4[NH2:28])[O:17]2)[CH3:31])[CH2:3]1)=[O:7]
Reactant: CNC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: COC(=O)C1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC(N(C)C[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (1.28 g crude), 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (2.0 g, 6.25 mmol) (Townsend et al Org Lett 2009, 11, 2976-2679) and Ti(iPrO)4 (1.78 g, 6.25 mmol) in MeOH (50 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (0.79 g, 12.50 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL), filtered, extracted with DCM (40 mL×3), dried over Na2SO4 and concentrated. The residue was purified by SGC (DCM:MeOH=12:1) to obtain title compound (1.7 g, Yield 63%). 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.21 (s, 1H), 6.20-6.18 (m, 1H), 5.52 (dd, J=1.5, 6.0 Hz, 1H), 5.00 (dd, J=3.0, 6.0 Hz, 1H), 5.33 (brs, 1H), 3.65-3.63 (m, 3H), 2.77-2.55 (m, 4H), 2.19-2.11 (m, 5H), 2.00-1.82 (m, 2H), 1.59 (s, 3H), 1.38 (s, 3H) ppm; ESI-MS (m/z): 433.2 [M+1]+.