Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH:7][C:8]([NH:10]C(=O)C2C=CC=CC=2)=[S:9])=[N:5][N:6]=1>[OH-].[Na+]>[CH3:1][C:2]1[NH:3][C:4]([NH:7][C:8]([NH2:10])=[S:9])=[N:5][N:6]=1
Reactant: Cc1nnc(NC(=S)NC(=O)c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nnc(NC(N)=S)[nH]1

Procedure:
The saponification of N-{[(5-methyl-4H-1,2,4-triazole-3-yl)amino]carbonothioyl}-benzamide in methanolic sodium hydroxide solution, could be performed even at room temperature. The N-(5-methyl-4H-1,2,4-triazole-3-yl)thiourea formed was alkylated with methyl iodide at room temperature and the resulting methyl N-(5-methyl-4H-1,2,4-triazole-3-yl)imidothiocarbamate was liberated by extraction of the organic phase with 1 N NaOH. Finally, the methyl N-(5-methyl-4H-1,2,4-triazole-3-yl)imidothiocarbamate was brought to reaction with 2,6-dimethoxybenzylamine in ethanol at 130° C. in the microwave (100 Watt) and the N-(2,6-dimethoxybenzyl)-N′-(5-methyl-4H-1,2,4-triazole-3-yl)guanidine was isolated following chromatographic purification on preparative HPLC (Merck: Chromolith RP-18E, 100-25; eluent water/acetonitrile/0.1 molar acetic acid). ESI-MS [M+H+]=291.15
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc([N+](=O)[O-])cc4)ccnc32)cc1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
A 20 mL sealable tube under nitrogen was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in from Example 5, Step B), 1-fluoro-4-nitrobenzene (0.0786 g, 0.557 mmol), Cs2CO3 (0.272 g, 0.836 mmol), and DMA (4 mL). The reaction mixture was heated to 90° C. for 2 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by Biotage 40S column eluting with Hexane/EtOAc 3:1, then EtOAc. Obtained the product (185 mg, 79%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.39 (d, J=5.1 Hz, 1H), 8.32 (d, J=9.4 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.40 (d, J=5.5 Hz, 1H), 3.77 (s, 3H), 2.58 (s, 3H). LRMS (esi pos) m/e 391 (M+1).
Reaction SMILES: I[C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C:20]#[CH:21].C(N(CC)CC)C.C(=O)(O)[O-]>CO.ClCCl.CN(C=O)C>[F:25][C:24]([F:27])([F:26])[C:23]([NH:22][CH2:19][C:20]#[C:21][C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:28]
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C#CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 67 %

Procedure:
A 100-mL three-necked flask was charged with 5-iodocytidine (2.66 g, 7.00 mmol, 1.00 equiv.), cuprous iodide (0.267 g, 1.40 mmol, 0.20 equiv.) and dry DMF (35 mL). After complete dissolution of the reaction mixture, propargyltrifluoroacetamide (3.17 g, 21.00 mmol, 3.00 equiv.), triethylamine (1.42 g, 14.00 mmol, 2.00 equiv.) and finally tetrakis (triphenylphosphine)palladium(0) (0.809 g, 0.70 mmol, 0.10 equiv.) were added to the reaction mixture under N2. The reaction was stirred at ambient temperature (around 19° C. to around 22° C.) under N2 for 18-24 h. The reaction was then diluted with 70 mL of 1:1 methanol-dichloromethane and the bicarbonate form of AGI X8 resin (12.00 g) was added. After stirring for about one h, the reaction mixture was filtered and the resin was washed with 1:1 methanol-dichloromethane. The combined filtrates were rapidly concentrated with a rotary evaporator. The residue was immediately purified by flash chromatography. Removal of solvent from the appropriate fractions afforded 1.84 g (67%) of 5-[3-(trifluoroacetamido)propynyl]cytidine as a light brown solid, which was confirmed by 1H-NMR.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10](Cl)=[O:11])[CH:6]=[CH:5][N:4]=[CH:3]1.[K+].[C:17]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH2:18]C([O-])=O.CCN(CC)CC.[Mg+2].[Cl-].[Cl-]>CC#N>[C:24]([O:23][C:17](=[O:22])[CH2:18][C:10]([C:9]1[CH:13]=[CH:14][N:15]=[C:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[CH:8]=1)=[O:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1ccnc(-n2ccnc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from 2-imidazol-1-yl-isonicotinoyl chloride hydrochloride [prepared by reaction of tert.-butyl 2-chloroisonicotinoate with imidazole and NaH in DMF at 80° C., treatment with formic acid at 50° C. and reaction with thionylchloride in toluene at 100° C.] and tert.-butyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a brown solid (10.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CO.ClCCl>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid piperidine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with 1% methanol/dichloromethane, 1.5% methanol/dichloromethane, 2% methanol/dichloromethane, and then 2.5% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [C:1]1([C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N+:23]([O-])=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:16]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.ClCCl>FC(C1C=CC=CC=1)(F)F>[C:42]([NH:46][C:24]1[CH:25]=[C:20]([C:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:8]=[C:7]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:10]=3)=[N:16][N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH:18]=2)[CH:21]=[CH:22][N:23]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
200 mg (0.4 mmol) of N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-(1-oxidopyridin-4-yl)-1H-pyrazol-3-yl]aniline were suspended in 50 ml of trifluoromethylbenzene and 210 μl (2 mmol) of tert-butylamine were added under stirring at room temperature. The mixture was cooled to 0° C. and 260 mg (0.8 mmol) of p-toluensulfonic anhydride were added. The reaction was maintained in the same conditions for 2.5 hours. Then the same amounts of reactants and 2 ml of dichloromethane to obtain a clear solution were added and after further 2 hours the reaction went to completion. The solvent was evaporated and the residue taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, giving 161 mg (73% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=1)[CH3:6])[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]=1[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1)[CH:31]=O)[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:30]3[CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]([N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[CH2:20][CH2:21]2)[CH:9]=1)([CH3:23])[CH3:6])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3cc(OCC)c(-n4cccc4)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[3-(piperidin-4-ylcarbamoyl)-phenoxy]-propionic acid ethyl ester (example 50i) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 578.3 (MH+).
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:12]1[C:11]([C:9]([OH:10])=[O:8])=[CH:16][N:15]=[CH:14][N:13]=1
Reactant: O=C(OCc1ccccc1)c1cnc(Cl)nc1C(F)(F)F
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C(O)c1cncnc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-trifluoromethyl-5-pyrimidine carboxylic acid benzyl ester in cyclohexene (3 mL, 30 mmole) and ethanol (9 mL) was treated with 10% palladium on carbon and the resulting mixture was heated to reflux for 1 h. The mixture was cooled to room temperature and filtered through a pad of Celite and concentrated to give a quantitative yield of a gummy, off-white solid. LR ES MS (C6H3F3N2O2): 191 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1.C([O-])(=[O:23])C.[Cs+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:23])[C:11]=3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(O)ccnc32)cc1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (7.00 g, 17.52 mmol, obtained from Example 84, Step D), cesium acetate (33.62 g, 175.2 mmol) and DMF (175 mL) was heated to 100° C. for 12 hours. The reaction was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (2.23 g, 79% yield) as a light orange solid. LRMS (APCI pos) m/e 381.9 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[Li+].[CH:12]([Mg]Cl)([CH3:14])[CH3:13].C(Br)C=C>C1COCC1.[Cu]I>[CH2:14]([C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1)[CH:12]=[CH2:13]
Reactant: CC(C)[Mg]Cl
Reactant: Fc1cc(Br)cnc1Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cnc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 5-bromo-2-chloro-3-fluoro pyridine (4.0 g, 19.05 mmol) at 0° C. was added isopropyl magnesium chloride lithium chloride complex (1.3 M THF solution, 24.8 mmol, 19.1 mL) over 10 min. After additional 10 min of stirring at 0° C., CuI (0.73 g, 3.81 mmol) was added, and the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (38.1 mmol, 3.3 mL) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with hexane and 10% ethyl acetate in hexanes to afford 2.5 g of 2 (77%) as a colorless oil. 1H NMR (CDCl3) δ 3.40 (2 H, d, J=6.60 Hz), 5.16 (2 H, m), 5.91 (1 H, m), 7.32 (1 H, dd, J=2.20, 9.00 Hz), 8.06 (1 H, d, J=1.76 Hz); LC/MS (M+1) 172.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][NH2:19])[CH2:3][CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1.[NH2:20][C:21]1[C:22]([C:29]([NH:31][C:32](=N)SC)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1>CC(O)C.CS(C)=O>[OH:15][C@H:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1[CH:16]=[CH:17][C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:18][NH:19]/[C:32](=[N:31]/[C:29]([C:22]3[C:21]([NH2:20])=[N:26][C:25]([NH2:27])=[C:24]([Cl:28])[N:23]=3)=[O:30])/[NH:1]2)=[CH:7][CH:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC[C@H](N)CCCc1ccc(OC[C@H](O)CO)cc1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Nc1nc(N)c(C(=O)/N=C2/NC[C@@H](CCCc3ccc(OC[C@H](O)CO)cc3)N2)nc1Cl
Temperature: 90 °C

Procedure:
To a stirred solution of (R)-3-[4-((R)-4,5-Diamino-pentyl)-phenoxy]-propane-1,2-diol (Intermediate 0) (32.8 mg, 0.122 mmol) in propan-2-ol (3 ml) is added 1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (45.8 mg, 0.122 mmol) and the resultant reaction mixture is heated at 90° C. for 18 hours. The reaction is allowed to cool to room temperature and diluted with DMSO (1.5 ml) and purified on a Waters 3000 preparative HPLC system (Microsorb™ C18, Water (0.1% TFA): MeCN). The fractions containing product are passed through a 1 g SCX-2 cartridge which is eluted with 1:1 Water:MeCN (20 ml), MeCN (20 ml) and 7M NH3 in MeOH (20 ml). The ammonia elutions are concentrated in vacuo to afford the title compound; [M+H]+ 464
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([S:33]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH:44]=[CH2:45])=[CH:39][C:38]=1[O:46][CH3:47])(=[O:35])=[O:34])[CH2:30][CH2:31][CH3:32].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:45]=[CH:44]/[CH2:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][S:33]([CH2:29][CH2:30][CH2:31][CH3:32])(=[O:34])=[O:35])=[C:38]([O:46][CH3:47])[CH:39]=2)[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Reactant: COC(=O)/C=C/c1ccc(I)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Oc1ccc(C/C=C/c2ccc(/C=C/C(=O)OC)c(OCc3ccccc3)c2)cc1OC
Temperature: 80 °C
Yield: 90.6 %

Procedure:
71 mg (0.2 mmol) of 2-(dicyclohexylphosphino)biphenyl and 23 mg (0.1 mmol) of palladium acetate are added to a solution of 2 g (5.07 mmol) of methyl(E)-3-(2-benzyloxy-4-iodophenyl)acrylate, 1.1 ml (7.6 mmol) of triethylamine and 2.9 g (5.07 mmol) of 4-allyl-2-methoxyphenyl 1-butane-1-sulfonate in 20 ml of dimethylformamide. The reaction mixture is heated at 80° C. for 4 hours. The reaction is treated by addition of 50 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvents are then evaporated off. The residue is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 2.53 g (91%) of methyl(E)-3-(2-benzyloxy-4-{(E)-3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propenyl}phenyl)acrylate are obtained in the form of a yellow oil.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][NH:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[NH:9].Br[C:14](=[CH:17]OC(C)C)[CH:15]=[O:16].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[CH:10]1([C:8]2[N:7]([CH3:6])[C:14]([CH:15]=[O:16])=[CH:17][N:9]=2)[CH2:12][CH2:11]1
Reactant: CNC(=N)C1CC1
Reactant: CC(C)OC=C(Br)C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cn1c(C=O)cnc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of 2.32 g (12.5 mmol) of N-methyl-cyclopropanecarboxamidine tetrafluoroborate in 4 mL of MeCN were added 2.41 g (12.5 mmol) of 2-bromo-3-isopropoxy-propenal, 5.1 g (37 mmol) of K2CO3, and 0.17 g (0.62 mmol) of 18-crown-6. The mixture was stirred at rt overnight, and then was concentrated and redissolved in EtOAc. Water was added to dissolve the salts, the layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined extracts were washed with a small amount of water and brine, dried over Na2SO4, filtered, concentrated, and chromatographed (35–85% EtOAc in hexanes) to provide 646 mg of 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde as a pale yellow oil.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]3[CH2:13][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])[CH2:15][CH2:16][N:11]3[C:10](=[O:25])[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][C:42]([NH2:44])=[O:43]>CN(C)C(=O)C.O>[O:25]=[C:10]1[N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:41][C:42]([NH2:44])=[O:43])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH:12]2[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:9]1
Reactant: O=C(C1CCNCC1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)CN1CCC(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)CC1
Yield: 50.9 %

Procedure:
A solution of hexahydro-1,1-diphenyl-7-[(4-piperidinyl)carbonyl]-3H-oxazolo[3,4-a]pyrazin-3-one hydrochloride (0.15 g, 0.34 mmol), potassium carbonate (0.12 g, 0.87 mmol), sodium iodide (51 mg, 0.34 mmol) and 2-chloroacetamide (38 mg, 0.41 mmol) in N,N-dimethylacetamide (3 mL) was stirred at room temperature for 26 hours. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated and dried to a solid. The residue was recrystallized from ethanol to obtain the title compound (80 mg, yield 50%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>C1(C)C(C)=CC=CC=1>[OH:15][C:11]1[CH:10]=[C:9]([NH:8][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(O)c1
Solvent: Cc1ccccc1C
Product: O=C(O)/C=C\C(=O)Nc1cccc(O)c1
Temperature: 50 °C

Procedure:
A dry 3-liter 3-neck round bottom flask was fitted with a stirrer and thermocouple arrangement. The system was flushed with nitrogen and charged with 211 grams (2.15 moles) of maleic anhydride dissolved in 800 ml of xylene. The maleic anhydride was heated with stirring at 50° C. to form a solution. 3-aminophenol (220 g, 2.02 moles) was then slowly added neat to the solution with vigorous stirring over a period of about 5 minutes. The flask was again flushed with nitrogen and sealed under a nitrogen balloon. The flask was held at 50°-55° C. with vigorous stirring for 4 hours. At the end of 4 hours, the stirring was continued and the flask and contents were cooled with tap water/wet ice to 10° C. The bright yellow-colored slurry was readily poured out of the neck of the flask and vacuum filtered through a No. 4 filter paper to give a wet filter cake. The product was dried at a temperature below 50° C. in a draft hood. The yellow product was a powder melting at 115° C. Specific gravity was 1.210.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)c1
Yield: 90.9 %

Procedure:
A solution of the product of Example 95B (2.87 g, 5.28 mmol), iron powder (1.5 g, 26.4 mmol) and ammonium chloride (0.43 g, 8.0 mmol) in an ethanol (75 mL), tetrahydrofuran (75 mL), and water (25 mL) solution was heated to reflux for 6 hours. The resultant mixture was diluted with ethanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as a yellow powder (2.47 g, 91%).