Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(=O)[N:7]([CH2:25][CH3:26])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14]C2C([CH:21]=1)=CC([N+]([O-])=O)=CC=2)=[O:12])(C)C.F[C:29]1[C:34]([NH:35][C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][C:43]([C:47]([NH:49][C:50]2[C:55](F)=[C:54](F)[C:53](F)=[C:52](F)[C:51]=2F)=[O:48])=[CH:42][CH:41]=3)=[O:37])=[C:33](F)[C:32](F)=[C:31](F)[C:30]=1F>CN(C=O)C>[CH2:25]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:31]2[C:32]([CH:21]=1)=[CH:33][C:34]([NH:35][C:36]([C:38]1[NH:39][C:40]3[C:45]([CH:46]=1)=[CH:44][C:43]([C:47]([NH:49][C:50]1[CH:55]=[C:54]4[C:53](=[CH:52][CH:51]=1)[NH:14][C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][CH2:25][CH3:26])=[CH:21]4)=[O:48])=[CH:42][CH:41]=3)=[O:37])=[CH:29][CH:30]=2)=[O:12])[CH3:26]
Reactant: CCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Reactant: O=C(Nc1c(F)c(F)c(F)c(F)c1F)c1ccc2[nH]c(C(=O)Nc3c(F)c(F)c(F)c(F)c3F)cc2c1
Solvent: CN(C)C=O
Product: CCNCCNC(=O)c1cc2cc(NC(=O)c3ccc4[nH]c(C(=O)Nc5ccc6[nH]c(C(=O)NCCNCC)cc6c5)cc4c3)ccc2[nH]1
Temperature: 55 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Compound 78 (127 mg, 0.336 mmol) was reduced to 79 by hydrogenation according to general procedure A in example 10. A mixture of above amine DS13a and 1H-indole-2,5-dicarboxylic acid bis-(pentafluorophenyl-amide) 74 (45 mg, 0.084 mmol) in 2 ml of anhydrous DMF under argon was stirred at 55° C. overnight. The solvent was evaporated to dryness. The residue was dissolved in 5 ml of TFA/anisole (8:2) and the mixture was kept at room temperature for 1 h. The product was precipitated by ether and purified by HPLC described in general procedure B in example 10 to give 76 (22 mg, 40%). ESI MS: 662.27 (M+H+), 331.64 (M/2+H+).
Reaction SMILES: [CH2:1]([O:5][Zr:6](OCCCC)([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].C(CC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:13]([O:12][Zr:6]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCO[Zr](OCCCC)(OCCCC)OCCCC
Solvent: CC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CCCCO[Zr](OCCCC)OCCCC

Procedure:
In 88 g of toluene was dissolved 38.3 g (0.1M) of tetra-n-butoxyzirconium, and 10.0 g (0.1M) of acetylacetone was gradually added to the resulting solution with stirring. An exothermic reaction of the mixture took place to give tri-n-butoxyzirconium acetylacetonato.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: COCC(=O)OC
Reactant: CC(N)c1ccc(Cl)cc1
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 2.5 h

Procedure:
At room temperature, a solution of 16.6 g (0.107 mol) of racemic 1 -(4-chloro-phenyl)-ethylamine in 41 g of methyl methoxyacetate is mixed with stirring with 1.2 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at 40° C. and the progress of the reaction is monitored by gas chromatographic sample analysis. After 2.5 hours, the conversion is 54%. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)-ethylamine has an ee value of 95.6%, while the (R)-enantiomer of N-(1-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 95.3%.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][CH3:34])[CH:27]=2)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][C:43](Cl)=[O:44])=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:41]([O:42][C:43](=[O:44])[N:33]([C:28]1[CH:27]=[C:26]([CH2:25][C@H:11]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:12](=[O:13])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:31]=[CH:30][C:29]=1[OH:32])[CH3:34])[C:38]1[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNc1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Solvent: c1ccncc1
Product: CN(C(=O)OCc1ccccc1)c1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude (2S)-2-benzenesulfonylamino-3-(4-hydroxy-3-methylamino-phenyl)-N-(4-phenyl-butyl)-propionamide of Step A (170 mg, 0.35 mmol) is dissolved in pyridine (4 mL) and Cbz-Cl (60 μL, 0.40 mmol) is added at 0° C. The mixture is stirred at RT overnight. The solvent is removed by evaporation and the residue is dissolved in EtOAc and purified by column chromatography (hexane/EtOAc) to provide {5-[(2S)-2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-hydroxy-phenyl}-methyl-carbamic acid benzyl ester.
Reaction SMILES: [C:1]1([N:7]([C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[O:10])N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Ca+2].[H-].[H][H].Cl.[OH-].[Na+]>CO.O>[NH:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2([CH2:14][CH2:13][CH2:12]2)[C:9]1=[O:10]
Reactant: [H][H]
Reactant: NN(C(=O)C1CCC1)c1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [H-]
Solvent: O
Solvent: CO
Product: O=C1Nc2ccccc2C12CCC2
Temperature: 230 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 1.50 g (7.89 mmol) cyclobutanecarboxylic acid N-phenylhydrazide and 530 mg (12.6 mmol) calcium hydride were mixed thoroughly and heated to 230° C. The mixture was stirred for 30 min at 230° C. and then cooled to RT again. The reaction mixture was carefully mixed with a solution of 7 mL water and 16 mL methanol. It was stirred for 1 h until no more hydrogen was released. Then the pH was adjusted to 1 with concentrated hydrochloric acid solution and the mixture was stirred for 1 h at 100° C. Using 4M sodium hydroxide solution the pH was adjusted to 3 and stirred overnight at RT. The precipitated substance was suction filtered and washed with 10 mL water. The mother liquor was evaporated down i.vac. and the residue was purified by preparative HPLC. The product fractions were combined, evaporated down i.vac. and dried.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[C:16]2[O:17][C:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:20]([CH2:33]O)[C:19]=3[C:15]=2[CH:14]=[C:13]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH:12]=1>ClCCl>[Cl:10][C:11]1[C:16]2[O:17][C:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:20]([CH2:33][F:7])[C:19]=3[C:15]=2[CH:14]=[C:13]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH:12]=1
Reactant: COc1ccc(CN2CCc3oc4c(Cl)cc(S(=O)(=O)c5ccccc5)cc4c3C2CO)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2CCc3oc4c(Cl)cc(S(=O)(=O)c5ccccc5)cc4c3C2CF)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
DAST (0.4 mL, 3.20 mmol) was slowly added to a stirred solution of the product of step B (180 mg, 0.36 mmol) in anhydrous dichloromethane (12 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature for 3 h then quenched by slow addition of aqueous sodium bicarbonate solution (10 mL). The organic layer was separated and the aqueous solution was further extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 to 7:3 hexanes/ethyl acetate) to give 6-chloro-1-(fluoromethyl)-2-(4-methoxybenzyl)-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (90 mg, 51%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.14 (d, J=1.2 Hz, 1H), 7.97-7.94 (m, 2H), 7.85 (d, J=1.5 Hz, 1H), 7.61-7.48 (m, 3H), 7.30-7.28 (m, 2H), 6.89-6.86 (m, 2H), 5.76-5.58 (m, 1H), 3.87 (s, 2H), 3.81 (s, 3H), 3.48-3.38 (m, 1H), 3.31-2.89 (m, 5H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CCCCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of hex-5-en-1-ol (20.0 g, 200 mmol) in CH2Cl2 (350 mL, 0.57 M) at 0° C. was added triethylamine (33.7 mL, 240 mmol, 1.2 equiv), DMAP (1.22 g, 10 mmol, 0.05 equiv) and then 4-Nitrobenzoyl chloride (39 g, 210 mmol, 1.05 equiv.). The reaction was stirred at rt for 2 h. The reaction mixture was quenched with a saturated NH4Cl solution and extracted 3 times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by combi-flash 2×120 g silica gel cartridge using gradient (0-5% in 5 min, 5-25% in 30 min, 25-40% EA/Hex in 10 min) to afford the desired product (35 g, Yield=70%) as a yellowish oil. 1H NMR (500 MHz, acetone-d6): δ 8.36 (d, 2H), 8.26 (d, 2H), 5.87-5.79 (m, 1H), 5.03 (d, 1H), 4.94 (d, 1H), 4.38 (t, 2H), 2.14 (m, 2H), 1.84-1.78 (m, 2H), 1.60-1.54 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH:13][CH2:14][CH3:15])=[CH:5][C:6]([N:9]([O:11][CH3:12])[CH3:10])=[N:7][CH:8]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>N1C=CC=CC=1>[CH2:14]([NH:13][C:4]1[C:3]([CH2:2][NH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:8][N:7]=[C:6]([N:9]([O:11][CH3:12])[CH3:10])[CH:5]=1)[CH3:15]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCNc1cc(N(C)OC)ncc1CCl
Solvent: c1ccncc1
Product: CCNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Yield: 85.7 %

Procedure:
5-(Chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (4.3 g, 18.7 mmol, from Example A19) and 4-fluoro-3-nitro-phenylamine (3 g, 19 mmol) were combined in pyridine (50 ml) by the method of Example A4 to provide N4-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2-methylpyridine-2,4-diamine (5.6 g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.65 (s, 1 H), 7.63 (s, 1 H), 7.34-7.29 (m, 1 H), 7.23-7.21 (m, 1H), 7.02-7.6.98 (m, 1 H), 6.84 (s, 1 H), 6.06 (s, 1 H), 4.18 (d, J=3.2 Hz, 2 H), 3.71 (s, 3 H), 3.31 (s, 3 H), 3.32 (q, J=7.2 Hz, 2 H), 1.18 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 350.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:7]=2[CH:18]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)N(CCNC(C)=O)CCO2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCN1CCOc2ccc(O)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, the compound obtained in Example 1 (342 mg; 1.37 mmol) is dissolved in 8 ml of distilled dichloromethane. The solution is cooled to −78° C., and then boron tribromide (4 eq.; 5.47 mmol; 5.17 μl) diluted with 5 ml of dichloromethane is slowly added. The mixture is left for one hour at −78° C. and then for 2 hours at ambient temperature. The reaction mixture is hydrolysed to pH 7 with a saturated sodium hydrogen carbonate solution and then the aqueous phase is extracted 4 times with dichloromethane. The organic phases are combined, and then removed under reduced pressure. The solid obtained is dissolved in a minimum amount of dichloromethane, precipitated in the presence of pentane, filtered, and then washed with an Et2O/pentane mixture.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[O:32])([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:8]([F:10])[CH:9]=1)(=[O:3])[CH3:2].[CH3:39][Li]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[O:32])([C:6]2[CH:5]=[C:4]([C:1]([OH:3])([CH3:39])[CH3:2])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: CC(=O)c1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of (R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 257, 20 mg, 0.037 mmol) in THF (1 mL) at 0° C. under argon was added dropwise CH3Li (1.4 M in Et2O, 0.04 mL, 0.056 mmol.). The reaction mixture was stirred at room temperature for 2 h, then quenched with sat. NH4Cl and 0.5 N HCl and the aqueous layer was extracted with EtOAc. The combined organic portions were washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 258, 8 mg, yield 39%). LCMS: RT=3.89 min [M+H] 559.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4Cl; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 7.51-7.45 (m, 2H), 7.21-6.96 (m, 6H), 6.68 (d, J=6.8 Hz, 2H), 6.61 (d, J=9.9 Hz, 1H), 5.43 (s, br, 1H), 5.17 (m, 1H), 4.01 (d, J=13.2 Hz, 1H), 3.85-3.62 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H).
Reaction SMILES: [CH:1]1([O:32][P:33]([O-:36])([O-:35])=[O:34])[CH:6]([O:7][P:8]([O-:11])([O-:10])=[O:9])[CH:5]([O:12][P:13]([O-:16])([O-:15])=[O:14])[CH:4]([O:17]P([O-])([O-])=O)[CH:3]([O:22]P([O-])([O-])=O)[CH:2]1[O:27]P([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[OH-].[Na+]>C(O)C>[C@H:4]1([OH:17])[CH:3]([OH:22])[C@@H:2]([OH:27])[C@@H:1]([O:32][P:33]([OH:36])([OH:35])=[O:34])[CH:6]([O:7][P:8]([OH:10])([OH:11])=[O:9])[C@@H:5]1[O:12][P:13]([OH:15])([OH:16])=[O:14]
Reactant: O=P([O-])([O-])OC1C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C1OP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=P(O)(O)OC1[C@H](OP(=O)(O)O)[C@H](O)C(O)[C@H](O)[C@H]1OP(=O)(O)O

Procedure:
100 ml of the fraction containing D-myo-inositol-1.2.6-triphosphate obtained in Example 15 was neutralized to a pH of about 7 with an aqueous solution of NaOH. After addition of 100 ml ethanol the volume of the solution was reduced by evaporation and the sodiumsalt was precipitated, centrifuged, recrystallized and dried in vacuum. The purified sodiumsalt of D-myo-inositol-1.2.6-triphosphate obtained was structurally confirmed by analysis with H-NMR.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][C:21]=1[CH3:29])[CH3:18].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:24]2[CH:25]=[C:20]([O:19][CH2:17][CH3:18])[C:21]([CH3:29])=[CH:22][C:23]=2[O:26][CH2:27][CH3:28])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCCC1CCCCC1
Reactant: CCOc1ccc(OCC)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(C(=O)CCCC2CCCCC2)c(OCC)cc1C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
4 g of 4-cyclohexylbutyryl chloride dissolved in 10 ml of CCl4 are added to a suspension of 2.9 g of AlCl3 in 40 ml of CCl4 at +4° C. 4.2 g of 2,5-diethoxytoluene in 20 ml of CCl4 are added dropwise. After 4 hours at +4° C., the reaction medium is poured into dilute ice-cold HCl solution. DCM is added, the phases are separated out by settling and the organic phase is then dried over MgSO4. After evaporation of the solvent, the product is purified by chromatography on silica H, eluting with toluene. 5.33 g of the expected compound are obtained: m.p.=49-50° C.
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].O.C(=S)=[S:26]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:26])[N:13]=1
Reactant: S=C=S
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 98 %

Procedure:
16g of adenosine 1-oxide monohydrate (53.3 mmol) was refluxed in 150 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 9.0 using Amberlite IRC-50 (H+-type). Water was then added thereto to make the total volume 400 ml. To this was added 100 ml of carbon disulfide, and the mixture was reacted in an autoclave at a temperature of 120° C for a period of 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance thus formed was recovered followed by concentration to dryness. The residue was dissolved in 125 ml of 2.5N aqueous ammonia, and any impurities contained were filtered out. A mixture of n-butanol and acetic acid (250 ml:125 ml) was added to the filtrate to crystallize the product to obtain 16.5 g of 2-thioadenosine having a melting point of 198° C (with decomposition) in a 98% yield. UV Absorption Spectrum: maxpH 1 238.5 nm (ε:13800) and 293 nm (ε:18400); maxpH13 243 nm (ε:19100) and 283 nm (ε:14000).
Reaction SMILES: [N-]=C=O.[CH:4]([NH:6][CH:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:10](=[O:16])[CH2:9][CH2:8]1)=O.C(Cl)(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[O:16]=[C:10]1[C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH:7]([N+:6]#[C-:4])[CH2:8][CH2:9]1
Reactant: O=CNC1CCC(=O)c2sccc21
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]C1CCC(=O)c2sccc21

Procedure:
Alternatively, formula (Ia) isocyanate can be prepared by reacting the N-formyl-4,5,6,7-tetrahydro-7-oxobenzo-[b]thiophen-4-amine of formula (IIIa) with phosgene in the presence of a tertiary amine, e.g. triethylamine, in an inert solvent such methylene chloride and other chlorinated hydrocarbons at a temperature between about 0° and 50° C and preferably between 15° and 30° C to obtain 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanide of formula (IV), which is then oxidized with dimethylsulfoxide (DMSO) in the presence of anhydrous p-toluenesulfonic acid (pTSA) at a temperature between about 25° and 75° C, and preferably 25° and 50° C. The above-described reaction sequence may be graphically illustrated as follows: ##SPC3##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][C:10](=[O:17])[CH:9]2[C:18](O)=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C=O.C(NCC)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][C:10](=[O:17])[C:9]2=[CH2:18])=[CH:6][CH:7]=1
Reactant: O=C(O)C1C(=O)OC(CCCO)C1c1ccc(Cl)cc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CC(=O)O
Product: C=C1C(=O)OC(CCCO)C1c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 89.6 %

Procedure:
4-(4-Chlorophenyl)-5-(3-hydroxypropyl)-2-oxotetrahydro-3-furancarboxylic acid (640 mg) was dissolved in a solution (5 ml) prepared from sodium acetate (105 mg), acetic acid (4 ml), formalin (2.92 ml) and diethylamine (1 ml), and the solution was heated on a water bath (100° C.) for 30 minutes. The reaction mixture was poured into ice water (20 ml) and extracted with ether. The extract was washed with 5% aqueous sodium hydroxide and water and dried over magnesium sulfate. The solvent was then distilled off. The residue was subjected to silical gel column chromatography, elution being carried out with chloroform to give 4-(4-chlorophenyl)-5-(3-hydroxypropyl)-3-methylenetetrahydro-2-furanone (512 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=1[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.CO.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[NH:20][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1)[C:25]#[N:26]
Reactant: Cc1cc(C#N)ccc1N
Reactant: Cn1ccc2c(Cl)ncc(C(=O)N3CCOCC3)c21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C#N)ccc1Nc1ncc(C(=O)N2CCOCC2)c2c1ccn2C
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-1-methyl-7-(4-morpholinylcarbonyl)-1H-pyrrolo[3,2-c]pyridine (100 mg), 4-amino-3-methylbenzonitrile (57 mg), cesium carbonate (163 mg), tris(dibenzylideneacetone)dipalladium (0) (7 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg) in 1,4-dioxan (2 ml) was heated to 100° C. under argon overnight. The reaction mixture was diluted with dichloromethane and washed with water, followed by saturated sodium chloride solution, then dried (MgSO4), filtered and evaporated. The residue was triturated with 2:1:1 methanol/dimethylsulfoxide/diethyl ether to yield an off white solid. This was dissolved in 1:1 methanol/dichloromethane and a solution of 1.0M hydrochloric acid in diethyl ether (1.4 ml) and the solvent evaporated to afford the title compound as an off white solid (36 mg).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:21])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)(=O)[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:20][O:19][C:13]1[CH:14]=[C:15]([O:17][CH3:18])[C:16]2[C:1]([CH3:2])=[C:4]3[N:5]([C:10](=[O:21])[C:11]=2[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9]3
Reactant: COc1cc(OC)cc(C(=O)N2CCCCC2C(C)=O)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c2c(C)c3n(c(=O)c2c1)CCCC3
Temperature: 25 °C

Procedure:
Reflux a solution of 2-acetyl-1-[3,5-bis(methoxy)benzoyl]piperidine (4.62 g), trifluoroacetic acid (3 ml), and carbon tetrachloride (97 ml) for 20 hours under nitrogen. Cool the solution to 25° C., and sequentially wash it with water, 1M sodium bicarbonate solution, and with water. Concentrate the dried, filtered organic solution, and cool it to induce crystallization. Recrystallize the resulting solid to obtain 8,10-bis(methoxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one, m.p. 165°-168° C. (from EtOAc).