Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])O.[Na+].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]#[N:24])=[CH:12][N:11]=1>C(O)C.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]([NH:2][OH:3])=[NH:24])=[CH:12][N:11]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(=N)NO
Yield: 82.8 %

Procedure:
The benzamidination carried out in this step follows the procedure reported by Meyer et al., Synthesis 2003, 6, pp. 899-905. To a stirred mixture of hydroxylamine hydrochloride (0.099 g, 1.43 mmol) and sodium hydrogen carbonate (0.119 g, 1.42 mmol) in ethanol (1.4 ml) and water (0.3 ml) was added 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.385 g, 1.29 mmol) and the mixture heated at reflux for 5 hours. A second portion of hydroxylamine hydrochloride (0.049 g, 0.71 mmol) and sodium hydrogen carbonate (0.060 g, 0.71 mmol) was added. After a further 2 hours the mixture was cooled, concentrated in vacuo, then diluted with water (10 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-N-hydroxy-4-isopropyl-2-methoxy-benzamidine (355 mg) as a yellow foam. This material was used directly without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-]>COCCOC.CO>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1
Temperature: 110 °C
Yield: 80 %

Procedure:
1 g (2.23 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.4 g (2.67 mM) of 4-methoxyphenylboronic acid, 1.6 g (4.46 mM) of carbonate resin and 0.02 g (0.004 mM) of [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane are mixed in 7 ml of DME and 5 ml of methanol. The reaction mixture is heated for 20 minutes at 110° C. by microwaves. It is filtered, the material on the filter is rinsed with methanol and the organic phases are concentrated. The product is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 98/2, then 70/30; v/v) to give the expected product in the form of a cream-colored powder with a yield of 80%.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([O:63][C:64]1[CH:69]=[N:68][CH:67]=[C:66]([CH:70]=C)[N:65]=1)([CH3:62])([CH3:61])[CH3:60].S([O-])([O-])=O.[Na+].[Na+].O>C(O)(C)(C)C>[C:59]([O:63][C:64]1[N:65]=[C:66]([CH:70]=[O:22])[CH:67]=[N:68][CH:69]=1)([CH3:62])([CH3:61])[CH3:60]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)Oc1cncc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
After adding 7.20 g of AD-mix-β to 60 ml of 50% aqueous tert-butanol, a solution of 1.00 g of 2-tert-butoxy-6-vinylpyrazine in tert-butanol (5 ml) was added and the mixture was stirred overnight at room temperature. Next, 8.40 g of sodium sulfite was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, and then water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methanol, an aqueous solution of 2.35 g of sodium periodate (20 ml) was added while stirring on ice, and stirring was continued at room temperature for 40 minutes. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (954 mg, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.N1C2C(=CC=CC=2)C=CC=1.[CH2:21]([OH:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[S:10])[O:23][CH2:21][CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: CCO
Solvent: c1ccc2ncccc2c1
Product: CCOC(=S)Nc1cccc(Cl)c1

Procedure:
A mixture of 45.5 gm (0.268 mol) of 3-chlorophenylisothiocyanate, 200 ml of anhydrous ethanol and 1 ml of quinoline was refluxed for 48 hours. Then, the reaction mixture was evaporated in an aspirator vacuum, the residue was taken up in ether, and the resulting solution was washed first with 5% hydrochloric acid and then thoroughly with water, dried, and evaporated again. After recrystallization from methanol/water, 49.5 gm (86% of theory) of colorless crystals with a melting point of 78°-79° C. were obtained.
Reaction SMILES: [C:1]1([C:7]2([C:20](=[O:23])[CH2:21][CH3:22])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O1CCOCC1.[Rh]>[CH:1]1([C:7]2([C:20](=[O:23])[CH2:21][CH3:22])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCC(=O)C1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
The following are introduced into a Parr bomb: 582 mg (1.83 mmol) of tert-butyl 4-phenyl-4-propionylpiperidine-1-carboxylate, 300 mg of rhodium on alumina and 0.5 mL of acetic acid in 15 mL of dioxane. The reaction mixture is placed under a hydrogen pressure of 6 bar and stirred at 80° C. for 16 hours. The reaction is stopped, filtered through Celite and washed with dichloromethane. The solvents are evaporated off and the residue is then chromatographed on silica gel (eluent: 95/5 heptane/ethyl acetate). 549 mg of tert-butyl 4-cyclohexyl-4-propionylpiperidine-1-carboxylate in the form of a colourless oil are obtained in a yield of 93%.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=[CH:2][CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: C#CCO
Reactant: CCCC[SnH](CCCC)CCCC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCCC[Sn](C=CCO)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To neat propargyl alcohol (1 ml) were added tributyl stannane (5.8 ml) followed by 1,1′-azobis(cyclohexanecarbonitrile) (213 mg). The mixture was heated for 2 h at 80° C., cooled to RT, and directly purified by column chromatography (EA/Hept 4/96 to 5/95) to afford 2.98 g of the desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(I)c1
Reaction time: 0.05 h
Yield: 86 %

Procedure:
40% Methanolic Triton B (0.07 mL, 0.15 mM) was added to a solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (60 mg, 0.13 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (30 mg, 0.19 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 60 mg (86%) of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6-7.0 (m, 11H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3500, 3350, 1727, 1642, 1291, 1236, and 772. MS (ES) m/e 515.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1O>COCCOC.ClCCl>[O:20]=[C:19]1[C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]3[C:11]=2[C:12](=[O:21])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]1=2
Reactant: Cc1ccc(N)nc1
Reactant: O=C1C(O)=C(Cl)C(=O)c2ccccc21
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc2nc3c(n2c1)C(=O)c1ccccc1C3=O
Yield: 16.9 %

Procedure:
0.55 g (5.08 mmol) of 2-amino-5-methylpyridine is added to a suspension of 0.45 g (2.16 mmol) of 3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in 15 mL of 1,2-dimethoxyethane. The reaction medium is brought to reflux for 21 h. After complete cooling, it is diluted with 120 mL of dichloromethane. The organic phase is washed successively with a saturated solution of sodium hydrogen carbonate and sodium chloride, then dried on sodium sulfate and evaporated under reduced pressure. The raw product obtained is purified on a medium-pressure column (support: silica; eluent: dichloromethane/heptane/ethyl acetate, 68/40/2) to produce 0.096 g of 6,11-dihydro-6,11-dioxo-2-methyl-naphtho[2',3':4,5]imidazo[1,2-a]pyridine in the form of yellow crystals after decoloration with animal black.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C(O)C.C(OB(C=C)OCCCC)CCC.[F:24][C:25]1([F:54])[CH2:53][CH:28]2[CH:29]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][O:51][CH3:52])=[CH:45][CH:44]=3)[O:30][C:31]3[C:36]([CH:27]2[CH2:26]1)=[CH:35][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:33][C:32]=3[C:41]#N>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:25]1([F:54])[CH2:53][CH:28]2[CH:29]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][O:51][CH3:52])=[CH:45][CH:44]=3)[O:30][C:31]3[C:32]([CH:41]=[CH2:1])=[CH:33][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:35][C:36]=3[CH:27]2[CH2:26]1
Reactant: COCOc1ccc(C2Oc3c(C#N)cc(OCOC)cc3C3CC(F)(F)CC32)cc1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB(OCCCC)OCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=Cc1cc(OCOC)cc2c1OC(c1ccc(OCOC)cc1)C1CC(F)(F)CC21
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Add 0.45 mL of toluene, 0.1 mL of absolute ethanol, and vinylboronic acid dibutyl ester (0.030 mL, 0.136 mmol) to a 4 mL vial containing preparation 16 (30 mg, 0.062 mmol) and Pd(PPh3)4 (7 mg, 0.0061 mmol). Bubble nitrogen through the solution for 5 min, seal tightly, and warm to 80° C. with stirring overnight. Dilute the solution with EtOAc and wash with brine. Back extract the aqueous solution with EtOAc. Wash the combined organic solutions with brine, dry over Na2SO4, filter, and concentrate. Adsorb the material to 500 mg of silica gel and purify by silica gel flash chromatography (4 g, 0-20% A/B, A=EtOAc, B=10% CH2Cl2 in hexanes) to afford 12 mg (0.028 mmol, 45%) of preparation 18. 1H NMR (400 MHz, CDCl3) δ 7.38-7.33 (m, 2H), 7.14-7.05 (m, 4H), 6.74 (d, 1H, J=2.6 Hz), 5.77 (dd, 1H, J=1.3, 18.1 Hz), 5.28 (dd, 1H, J=1.3, 12.3 Hz), 5.20 (s, 2H), 5.15 (d, 1H, J=10.1 Hz), 5.13 (d, 1H, J=9.7 Hz), 5.02 (bs, 1H), 3.67 (dt, 1H, J=3.1, 11.0 Hz), 3.50 (s, 1H), 2.89 (m, 1H), 2.74 (m, 1H), 2.30 (m, 1H), 2.17 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)[CH3:22])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
To a cooled (˜15° C.) and stirred solution of 18 g (57.4 mmol) of trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 135 ml of dioxane was added 63.2 mL (63.2mmol, 1.1 eq) of aqueous 1 M NaOH within 5 min. The reaction was homogenised with 13 mL of MeOH and 28.7 mL (28.7 mmol, 0.5 eq) of aqueous 1 M NaOH after 3 h, then stirred for additional 1.5 h. The reaction was evaporated to remove the dioxane, partitioned between Et2O (×3)/H2O, dried over Na2SO4 and evaporated to yield 17.13 g (quantitative) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester, MS: 272 (MH+).
Reaction SMILES: [Cl-].[NH4+].[C:3]([O:7][C:8](=[O:46])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:19]2[CH:20]=[CH:21][C:22]([I:24])=[CH:23][C:18]=2[C:17](=[O:25])[N:16]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[N+:35]([O-])=O)[CH3:27])[CH:15]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C:14]1=[O:45])([CH3:6])([CH3:5])[CH3:4]>O.C(O)C.[Fe]>[C:3]([O:7][C:8](=[O:46])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:19]2[CH:20]=[CH:21][C:22]([I:24])=[CH:23][C:18]=2[C:17](=[O:25])[N:16]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[NH2:35])[CH3:27])[CH:15]([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[C:14]1=[O:45])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(c1ccc(Cl)cc1[N+](=O)[O-])N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)C1c1ccc(Cl)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(c1ccc(Cl)cc1N)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)C1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of ammonium chloride (220 mg, 4.3 mmol) in water (2.5 mL) was added to a solution of 5-[3-(4-chlorophenyl)-4-[1-(4-chloro-2-nitrophenyl)ethyl]-7-iodo-2,5-dioxo-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester (230 mg, 0.306 mmol) in ethanol (5 mL). The resulting solution was heated to 80° C. and iron (200 mg, 3.58 mmol) was added. After 2 h at 80° C., the reaction mixture was cooled at room temperature, filtered through celite and evaporated. The residue was partitioned between ethyl acetat and water, dried (Na2SO4), and evaporated. Chromatography on silica (EtOAc/hexanes, 1:1) afforded the title compound (210 mg, 95%) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H, 3 CH2)), 1.57–1.63 (m, 4H, 2 CH2), 1.74 (d, J=7.2 Hz, 3H, CH3), 2.24 (t, J=7.2 Hz, 2H, CH2), 3.63–3.70 (m, 1H, CH), 4.28–4.35 (m, 1H, CH), 4.75 (br s, 2H, NH2), 5.28 (s, 1H, CH), 6.27 (q, J=7.2 Hz, 1H, CH), 6.60–6.69 (m, 5H, ArH), 6.90 (d, J=9.2 Hz, 2H, ArH), 7.20 (d, J=8.4 Hz, 1H, ArH), 7.49 (dd, J=8.8 Hz, J=2.4 Hz, 1H, ArH), 7.93 (d, J=2.0 Hz, 1H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C32H34Cl2IN3O4: 721.0; found: 722.0 (M+H)+.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:33]([O:40][CH:41]1[CH:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:42]1=[O:72])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1>[S:28]1[C:24]([CH2:23][C:15]2[CH:14]=[C:13]([C:42]3([OH:72])[C@H:41]([O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C@@H:46]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C@@H:45]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[O:43]3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]1=2
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: Brc1cc(Cc2cc3ccccc3s2)cc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cc(Cc3cc4ccccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 1.58 ml, 2.53 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-ylmethyl)-benzo[b]thiophene (0.81 g, 2.29 mmol) in anhydrous THF (15 ml) at −78° C. over five minutes. The reaction mixture was stirred at −78° C. for 5 minutes, and then a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran-2-one (1.36 g, 2.52 mmol) in anhydrous THF (10 ml) was added dropwise thereto at −78° C. and the reaction solution was stirred at −78° C. for 2 hours. To the obtained reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with diethyl ether and the organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.4 g, 75%).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.O[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1>O>[Cl:3][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: OCC1COc2ccccc2O1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: ClCC1COc2ccccc2O1

Procedure:
In a three neck flask fitted with a stirring device, 218 g thionyl chloride are mixed with 1000 g pyridine while cooling. They are added further, portionwise 500 g 2(hydroxy methyl) (2,3-dihydro [4H] 1,4-benzodioxin) while keeping the inner temperature below 20°. When the reaction is completed, the mixture is heated at 100° for 3 hours then poured into water and extracted with chloroform. The solvent is distilled off and the raw residue is purified by fractional distillation under reduced pressure. 340 g of the chloromethylated derivative are obtained. It boils at 85°-90°/0.2 mm Hg.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[O:8][CH:7]=1.C(OCC)C>CS(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH:7]=[C:6]([CH2:5][C:1]#[N:2])[C:10]=2[CH:11]=1
Reactant: [C-]#N
Reactant: Fc1ccc2occ(CCl)c2c1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CCc1coc2ccc(F)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing. A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g). A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 mL) was heated to 80° C. followed by quick addition of a solution of 3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL). The mixture was kept at 80° C. for ½ h and then poured onto ice. Standard work-up with diethyl ether gave a dark crystalline material, 5-fluorobenzofuran-3-ylacetonitrile (8.8 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:13])([CH3:12])[C:9]([NH:20][C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C(=O)O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)C(C)(C)c2cccc(Br)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(6-bromopyridin-2-yl)-2-methylpropanoic acid (120 mg, 0.49 mmol) in dimethylformamide (3 mL) was charged with 1-methyl-1H-pyrazol-4-amine (48 mg, 0.49 mmol). Dimethylaminopyridine (60 mg, 0.49 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to afford the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N:7]1[C:11](=O)[CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8]1>O>[Cl:3][C:11]1[N:7]([CH3:6])[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1[nH]c(-c2ccccc2)cc1=O
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1Cl
Reaction time: 30 h
Yield: 66.4 %

Procedure:
To a solution of phosphorous oxychloride (2,015 g, 19 moles) is added solid 1-methyl-3-phenylpyrazolin-5-one (2,073 g, 11.9 moles) with stirring and warming. At 100°C. the mixture becomes homogeneous. The reflux temperature rises from 119°C. to 143°C. over a period of 30 hours. After cooling the mixture is poured into ice and water (8 l) with stirring. After 4 hours the slurry is filtered and the filter cake added to 4 l of water containing 1.5 l of 10% sodium hydroxide solution with stirring. Removal of the solid by filtration followed by a recrystallization from hexane yields 1,523 g of product, having a melting point ranging from 61°C. to 62°C.