Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)CC2
Temperature: 130 °C
Yield: 33.9 %

Procedure:
A mixture of 0.5 g 6-methoxy-1-indanone, 1.23 g oxindole and 2.7 ml piperidine in 4 ml of dimethylforamide was heated in a sealed tube 130° C. for 3 days to yield a greenish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was precipitated from methylene chloride/hexanes (3×) to afford 290 mg 3-(6-methoxyindan-1-ylidene)-1,3-dihydroindol-2-one as a yellowish-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40].[OH-].[Na+].Cl>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([OH:41])=[O:40]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(F)cc4)cc3CCc3ccccc3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(F)cc4)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
The oil obtained in Example 142 was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and 2 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (61 mg, yield 11%, 2 steps) as colorless crystals. 1H NMR (CDCl3) δ: 2.62 (2H, t, J=7.5 Hz), 2.79-2.93 (6H, m), 4.98 (2H, s), 5.24 (2H, s), 6.37 (1H, s), 6.59-6.68 (2H, m), 7.03-7.14 (7H, m), 7.18-7.38 (5H, m), 7.76 (2H, dd, J=8.9, 5.5 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+].CC(=O)CC>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][I:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: ICC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Yield: 91.2 %

Procedure:
First, 6 g of 2,2-bis(6-benzyloxyhexyl)ethyl bromide, 2.19 g of sodium iodide, and 150 ml of 2-butanone were placed in a 300 ml flask. The mixture was stirred under reflux for 16 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 6 g of 2,2-bis(6-benzyloxyhexyl)ethyl iodide (Y: 91.2%). The compound thus obtained had a purity of 95.3% by HPLC.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[N+:14]([O-])=O)[CH:9]=[C:8]([F:17])[C:7]=1[F:18]>C1COCC1>[CH2:1]([NH:4][CH:12]([C:10]1[CH:9]=[C:8]([F:17])[C:7]([F:18])=[C:6]([F:5])[CH:11]=1)[CH2:13][NH2:14])[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])/C=C/c1cc(F)c(F)c(F)c1
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(CN)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Allylamine (9.8 mL) was added to a solution of 1,2,3-trifluoro-5-((E)-2-nitrovinyl)benzene (6.6 g) in THF (30 mL). The reaction solution was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. Zinc powder (10.6 g) was added to a solution of the residue in ethanol (35 mL) and concentrated hydrochloric acid (35 mL) at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes and at room temperature for 15 hours. The reaction solution was added to ice-cold aqueous ammonia, and the reaction mixture was subjected to extraction with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 7.52 g of a crude product of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]#[N:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[NH2:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (36.8 g, 0.10 mol) was dissolved in anhydrous THF (350 mL), and the solution was heated under reflux under a nitrogen atmosphere. A solution of BH3.Me2S (30 mL, 0.30 mol) in THF was added drop wise, and stirring was continued under reflux overnight. The resulting solution was cooled to room temperature. The reaction was quenched by careful, drop wise addition of MeOH until bubbling ceased. After evaporation of the solution, the crude product was obtained (70 g), which was used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)o1
Temperature: 25 °C

Procedure:
To a stirred suspension of 8.43 g (44.14 mmol) of 5-bromo-2-furoic acid in 100 ml absolute ethanol was added 4 ml of thionyl chloride. This mixture was stirred at reflux for 3 hours and at room temperature for 18 hours. The solvent was removed in vacuo, the residual oil treated with 100 ml water and extracted with 3×75 ml ether. The combined either extracts were washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue kugelrohr distilled (60° C.; 0.4 mm) to give the captioned compound as a colorless oil. PRM (CDCl3); δ1.35 (3H, t, J~7 Hz), 4.37 (2H, q, J~7 Hz), 6.45 (1H, d, J~4 Hz), 7.1 (1H, d, J~4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](Br)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(OCC)(=O)C.[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:33]#[N:34])=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2C#N)CC1

Procedure:
Under argon atmosphere 47 mg (0.4 mmol) of Zn(CN)2 and 23 mg of (0.02 eq) Pd(PPh3)4 were added to a solution 62 mg (0.4 mmol) of 4-(5-bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in DMF. The reaction was heated for 5 minutes to 150° C. in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through celite, washed with ethyl acetate and concentrated to yield 176 mg of compound 15.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:24])[CH:17]=[C:16]([C@@H:25]([NH:27][C:28]2[N:36]=[CH:35][N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][NH:32]3)[CH3:26])[N:15]=1.O>C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([O:10][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[N:15][C:16]([C@@H:25]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]3[C:29]=1[N:30]=[CH:31][NH:32]3)[CH3:26])=[CH:17]2
Reactant: CC(C)N1CCC(O)CC1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(Oc2nc([C@H](C)Nc3ncnc4[nH]cnc34)cc3cccc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 1-isopropylpiperidin-4-ol (120 mg, 0.83 mmol, 1.2 eq) in THF (10 mL) at 0° C., NaH (60% in mineral oil, 33.2 mg, 0.83 mmol, 1.2 eq) was added and the resulting mixture was stirred for 10 min. To this mixture, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine 38 (250 mg, 0.70 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux overnight, cooled to RT and then poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (5% MeOH-DCM) to afford the product, (S)—N-(1-(8-chloro-1-(1-isopropylpiperidin-4-yloxy)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 47. ESI-MS m/z: 466.2 [M+H]+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[F:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([S:19]([F:18])(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Cl)c1ccc(S(=O)(=O)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Yield: 95.2 %

Procedure:
A solution of glycine tert-butyl ester hydrochloride (300 mg, 1.79 mmol) (Aldrich), Et3N (250 μL, 1.79 mmol), and 4-(fluorosulfonyl)benzoyl chloride (400 mg, 1.79 mmol) (Aldrich) in 9 mL of dry N,N-dimethylformamide was stirred at room temperature under a nitrogen atmosphere for 12 h. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with distilled water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude (4-fluorosulfonyl-benzoylamino)-acetic acid tert-butyl ester (541 mg, 95%) as an oil that solidified upon sitting at room temperature. The crude (4-fluorosulfonyl-benzoylamino)-acetic acid tert-butyl ester was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([O:28]C(C)(C)C)=O)[C@H:21]3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14]2)=[CH:9]1.[OH-].[Na+].[C:35]([NH:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1C(O)=O)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>O>[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([C:45]4[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=4[NH:43][C:35](=[O:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:28])[C@H:21]3[C:20]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[NH:14]2)=[CH:9]1
Reactant: O=C(Nc1ccccc1C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21
Agent: CCOC(=O)OC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1ccccc1C(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 43.1 %

Procedure:
TFA (2 ml) was added to tert-butyl (3aR*,4R*,9bR*)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (219 mg, 0.61 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, and the mixture was basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 ml), 2-(benzoylamino)benzoic acid (162 mg, 0.67 mmol) and triethylamine (124 mg, 1.2 mmol) were added. DEPC (99 mg, 0.61 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-3:1, v/v) to give the title compound (126 mg, 43%) as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C=O)C.C1COCC1.CN(C=O)C>[C:31]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:33])[CH3:32]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N2, the suspension was cooled down to −15° C. and a solution of acetyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 min at −15° C. then for 6 h at room temperature. Water (0.5 mL) was added at 0° C., solvent was removed, and the residue was diluted with MeOH, filtrated and purified by preparative HPLC to give N-(1-acetyl-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]diox ol-5-yl)cyclo-propanecarboxamide. 1H NMR (400 MHz, DMSO) δ 8.9 (s, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.28 (dd, J1=2.1 Hz, J2=9.0 Hz, 1H), 7.01 (d, J=1.5 Hz, 1H), 6.93 (dd, J1=1.7 Hz, J2=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.54 (bs, 1H), 6.02 (s, 2H), 2.80 (s, 3H), 1.42-1.40 (m, 11H), 1.06-1.05 (m, 2H). MS (ESI) m/e (M+H+) 419.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>COCCO>[ClH:1].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH:15][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2ccsc12
Solvent: COCCO
Product: Brc1cccc(Nc2ncnc3ccsc23)c1
Product: Cl
Temperature: 79 °C
Yield: 72.2 %

Procedure:
A mixture of 4-chlorothieno(3,2-d]-pyrimidine (135 mg, 0.79 mmol) and 3-bromoaniline (95 μL, 0.89 mmol) in 2-methoxyethanol (2 mL) is heated to 79° C. for 30 min. The resulting precipitate is filtered and washed with CH2Cl2 to yield 4-(3-bromo-anilino)thieno[3,2-d]pyrimidine hydrochloride (195.5 mg, 72%) a s a light yellow solid. 1H NMR (DMSO) δ 11.33 (1H, s), 8.94 (1H, s), 8.23 (1H, s), 8.53 (1H, d, J=5.3 Hz), 8.07 (1H, s), 7.77 (1H, d, J=7.9 Hz), 7.6 (1H, d, J=5.3 Hz), 7.48 (2H, m).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.C(Cl)(Cl)Cl.C[OH:64]>C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@@:3]12[O:64][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: CO
Reactant: CCC1=C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](OC(C)=O)[C@]3(O)C(=O)OC)C2)C1
Solvent: ClC(Cl)Cl
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
A solution of 50 mg of "anhydrovinblastine" III in 3 cm3 of chloroform at ambient temperature (20° C.) is stirred in the air in the presence of 50 mg of silica for 72 hours then diluted with 20 cm3 of chloroform/methanol 85/15 mixture, filtered and evaporated under reduced pressure. The mixture obtained is purified by chromatography on a thick layer of silica under the same conditions as in Example 1 and provides 13.8 mg of leurosine I and 20 mg of "anhydrovinblastine" III which may be recycled.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2].Cl.[NH2:18]O>CN1CCCC1=O.C(OCC)C>[C:9]([C:7]1[CH:6]=[C:5]([CH3:11])[C:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([CH2:1][CH3:2])[CH:8]=1)#[N:18]
Reactant: CCc1cc(C=O)cc(C)c1CCC(=O)O
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCc1cc(C#N)cc(C)c1CCC(=O)O
Yield: 94.1 %

Procedure:
A solution of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-propionic acid (1.67 g, 7.58 mmol) and hydroxylamine hydrochloride (780 mg, 11.36 mmol) in 1-methyl-2-pyrrolidone is heated to 80° C. for 30 min in the microwave (300 W, active cooling during irradiation). The reaction mixture is diluted with diethyl ether and washed with water and brine. The organic extract is dried over Na2SO4, filtered and evaporated to give 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (1.55 g) as a beige solid; LC-MS: tR=0.89 min, 1H NMR (D6-DMSO): δ 12.25 (s, 1H), 7.45 (s, 2H), 2.91-2.84 (m, 2H), 2.67-2.59 (m, 2H), 2.35-2.30 (m, 5H), 1.14 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([CH3:15])=[CH:13][C:12]3[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=3[CH:6]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#CC(O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Product: CC(=O)Oc1ccc(C#CC(O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Yield: 24.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.28 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol with 1.44 g (5.5 mmol) of 4-iodophenyl acetate, 480 mg (25%) of the expected compound, with a melting point of 129°-130° C., were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)N1C=COc2ccc(C=O)cc21
Product: CC(C)(C)OC(=O)N1C=COc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 6-Formyl-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (intermediate 63) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2](=[N:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])C(=O)SC.S(Cl)(Cl)(=O)=O.[Cl:23][CH2:24][Cl:25]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:7]=[SH:2]([CH3:1])=[C:24]([Cl:25])[Cl:23])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: ClCCl
Reactant: CSC(=O)S(C)=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Product: C[SH](=NS(=O)(=O)c1ccc(Cl)cc1)=C(Cl)Cl
Temperature: 35 °C

Procedure:
The N-(4-chlorophenylsulphonyl)-iminodithiocarbonic acid-S,S-dimethyl ester (1000 g) obtained in the manner described is suspended in 1000 ml of dichloromethane, and 290 ml of sulphonyl chloride (3.6 moles) is added dropwise to the suspension, whereupon a yellow solution is obtained with generation of SO2. This solution is heated for about 2 hours at a temperature of 35° C. The solvent as well as the formed methanesulphonyl chloride and unreacted sulphonyl chloride is distilled off in a Rotovap, and the crystallised residue is taken up in hexane. After filtration with suction there is obtained N-(4-chlorophenysulphonyl)-S-methyl-iminothiocarbonic acid chloride: m.p. 86°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]#[C:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].[CH3:17][CH2:18][O:19][C:20](/[C:22](/Cl)=[N:23]\[OH:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:24][N:23]=[C:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])[C:11]=1[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: CSc1ccc(C#CC(=O)C2CC2)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(-c2ccc(SC)cc2Cl)c1C(=O)C1CC1
Yield: 35.5 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphenyl)phenyl]-3-cyclopropylprop-1-yn-3-one (1.39g) and ethyl chloro-oximidoacetate (0.84g) in toluene was stirred and heated at reflux overnight. It was cooled and evaporated to dryness. The residue was purified by chromatography eluted with a mixture of hexane and dichloromethane, followed by ether to give ethyl 5-[2-chloro-4-(methylsulphenyl)phenyl]-4-cyclopropylcarbonylisoxazole-3-carboxylate (compound 9, 0.72g) as an orange solid, m.p. 50° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[O:3][C:4]1[CH:9]=CC[CH2:6][CH:5]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]#[C:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][C:14]1[CH:9]=[C:4]([O:3][Si:2]([CH3:11])([CH3:10])[CH3:1])[CH:5]=[CH:6][C:13]=1[C:12]([O:17][CH3:18])=[O:16]
Reactant: CC#CC(=O)OC
Reactant: C[Si](C)(C)OC1=CCCC=C1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(O[Si](C)(C)C)cc1C
Temperature: 150 °C

Procedure:
A 50 mL round bottom flask equipped with magnetic stir bar and condenser was charged with 6.0 g of 2-trimethylsilyloxy-1,3-cyclohexadiene, 3.5 g methyl tetrolate in 3 mL dry toluene. The reaction was heated to 150° C. for 50 hours at which point 1H-NMR indicated no starting diene. The raction was concentrated in vacuo to provide 5.7 (67%) methyl 2-methyl-4-trimethylsilyloxybenzoate.