Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[CH3:3][C@@:4]12[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:7]1[CH2:6][CH2:5]2)[CH2:21][CH2:20][C:18](=[O:19])[CH:17]=3.O=O.S([O-])([O-])(=[O:27])=S.[Na+].[Na+].[C:32](#N)C>CO>[CH3:3][C@@:4]12[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:14][C:15]([C:16]3[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=3[C@H:7]1[CH2:6][CH2:5]2)=[O:27].[CH3:32][O:19][CH3:18]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC#N
Reactant: O=S([O-])([O-])=S
Agent: II
Agent: O=O
Agent: [Na+]
Solvent: CO
Product: COC
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C(=O)C[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
Iodine (508 mg, 2 mmol) and 19-nor-4-androstene-3,17-dione (272 mg, 1 mmol) were dissolved in a mixture of acetonitrile (12 mL) and methanol (3 mL), to thereby form a reaction mixture. The reaction mixture was stirred for two hours while oxygen was introduced (50 mL/min) thereto under cooling in an ice-bath. The resultant mixture was maintained at room temperature, and after stirring of the mixture for a further 1.5 hours, introduction of oxygen was stopped and the mixture was refluxed for one hour. The reaction mixture was cooled to room temperature, and an aqueous solution of sodium thiosulfate was added to the mixture. The mixture was extracted with chloroform, and the organic phase was washed sequentially with an aqueous solution of sodium bicarbonate and saturated brine. The washed matter was dried over magnesium sulfate anhydrate, filtered, and evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform), to thereby yield 230 mg of the title compound (yield: 77%).
Reaction SMILES: [C:1](#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9].[CH2:10]([OH:13])[CH2:11][OH:12]>>[C:1]([O:12][CH2:11][CH2:10][OH:13])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: O
Reactant: OCCO
Product: O=C(OCCO)c1ccccc1

Procedure:
A solution of benzonitrile (103g) in ethylene glycol (310g) was heated at reflux under substantially anhydrous conditions for 3 days. The reaction mixture was cooled and added to a mixture of ice and water (about 300ml). The resulting mixture was extracted with ether (3 × 300ml) and the combined ether extract back-washed with water (2 × 300ml) and then with a saturated sodium chloride solution (300ml). The ether solution was dried over anhydrous sodium sulfate. The ether was evaporated and the residual oil distilled to give 108g (65% of theoretical) of ethylene glycol monobenzoate, b.p. 132°-135° C./1.5 mm Hg.
Reaction SMILES: [OH:1][C:2]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])[C:3]([F:6])([F:5])[F:4].[H][H].[NH3:17]>[Rh]>[NH2:17][CH:11]1[CH2:12][CH2:13][CH:8]([C:2]([OH:1])([CH3:7])[C:3]([F:6])([F:5])[F:4])[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CC(O)(C1CCC(=O)CC1)C(F)(F)F
Reactant: N
Agent: [Rh]
Product: CC(O)(C1CCC(N)CC1)C(F)(F)F

Procedure:
11.1 g (53 mmol) of 4-(2-hydroxy-1,1,1-trifluoro-2-propyl)cyclohexanone were subjected to reductive amination in 150 ml of ammonia-saturated methanol in the presence of 2.3 g of rhodium (5% on charcoal) with 50 bar of hydrogen. 9.0 g (80.1% of theory) were obtained of a colorless oil which was reacted without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:10]1[C:6]2[C:4](=[O:3])[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12][C:7]=2[NH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCCCC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A stirred solution of 4-methyl-2-[2-(2-piperidin-1-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.07 g, 10 mmol) in toluene (50 ml) was added dropwise slowly with 2M trimethyl aluminum in toluene (10 ml, 20 mmol) under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and heated to reflux for another 4 hours. The reaction mixture was cooled down to 0° C. in ice/water bath, added with cold water (50 ml) and stirred for 5 minutes. The mixture was adjusted to pH12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (40 ml×3). The combined organic extracts were washed with brine (15 ml), filtered through a pad of Celite. The filtrate was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.29 g) as a red oil which was used as such.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:6][C:7]=1Cl.[NH3:15]>O>[NH2:15][C:7]1[N:6]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[Cl:1]
Reactant: N
Reactant: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Solvent: O
Product: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Temperature: 80 °C

Procedure:
A mixture of 5,6-dichloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step C1 or C2) (5.1 g, 22 mmol), water (30 mL) and aqueous ammonia (28%, 8 g, 130 mmol) was heated at 80° C. for 3 h. The solution was concentrated at 50° C. and 70 torr (9.3 kPa) pressure to about half volume to remove most of the excess ammonia. The resulting slurry was stirred at 20° C., acidified to pH 2 with aqueous hydrochloric acid, cooled to 5° C. and filtered. The isolated solid was dried in a vacuum oven to afford the title product (4.2 g), a compound of the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:32]1[CH:33]=[N:34][CH:35]=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:34]1[CH:33]=[C:32]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[O:13][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[N:10][N:11]=3)=[CH:15][CH:16]=2)[CH:37]=[N:36][CH:35]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Reactant: Brc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Clc1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 40.8 %

Procedure:
4-{5-[(3-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (95.4 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 30 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (74.7 mg). Yield 40.8%.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[O-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl.O>CO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(CCl)c1
Reactant: O=C(O)c1cccnc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(CSc2ncccc2C(=O)O)c1
Reaction time: 14 h

Procedure:
A suspension of 4.65 g (0.03 mole) of 2-mercaptonicotinic acid in 100 ml of methanol was cooled in ice as 3.24 g (0.06 mole) of sodium methoxide was added. The resulting solution was left at ice-temperature as 4.68 g (0.03 mole) of 3-methoxybenzyl chloride was added over 5 minutes. The reaction mixture was stirred for 14 hours and the reaction set solid. The addition of 50 ml of water caused solution and an excess of acetic acid precipitated 7.55 g (92% of theory) of 2-(3-methoxybenzylthio)nicotinic acid. Recrystallization was effected from ethyl acetate; m.p. 156°-157° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[C:34]([CH3:36])[C:31]([CH:32]=[O:33])=[C:30]([CH3:37])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[C:30]([CH3:37])=[CH:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:35][C:34]=1[CH3:36])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C=O
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1c(C)cc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 1 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2,6-dimethyl-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as colorless liquid. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:11](=[O:22])[C:12](=[O:21])[C:13]=2[NH:14][CH:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[O:21]=[C:12]1[C:11](=[O:22])[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([C:30]#[N:31])=[CH:3][CH:4]=2)=[C:13]1[NH:14][CH:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(Nc1c(/C=C/c2ccc(Br)cc2)c(=O)c1=O)C(C)(C)C
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: Cc1ccccc1
Product: CC(Nc1c(/C=C/c2ccc(C#N)cc2)c(=O)c1=O)C(C)(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
The title compound was prepared via cyano-debromination (Tschaen, Synth. Comm. 1994, 24, 887) of the title compound of Example 26. To a mixture of 3-[(E)-2-(4-bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (400 mg, 1.10 mmol) and zinc (II) cyanide (77.8 mg, 0.662 mmol) in DMF (1.20 mL) was added tetrakis(triphenylphosphine)palladium (0) (76.6 mg, 0.0662) under an atmosphere of Argon. The reaction mixture was heated to 100° C., stirred 18 hours, then worked up by dilution with toluene (150 mL), followed by consecutive extraction with ammonium hydroxide (3×50 mL) and brine (50 mL). The organic phase was further diluted with ethyl acetate (300 mL), dried over MgSO4, filtered through a short pad of diatomaceous earth, and then concentrated onto silica gel. Submission to flash chromatography (multiple gradient elution with ether-petroleum ether) afforded a yellow solid which was triturated with ether-hexanes. Drying under high vacuum at 60° C. yielded the title compound (248 mg, 73%) as a hydroscopic yellow solid (1H NMR in DMSO-d6 suggested the presence of amide rotamers in a ratio of approximately 4:1): m.p. 240.2-241.0° C.; 1H NMR (DMSO-d6) δ 8.96(d,1H), 7.83(m,4H), 7.64(d,1H), 7.48(d,1H), 4.03(dq,1H), 1.20(d,3H), 0.90(s,9H); IR (KBr) 3450, 3250, 3290, 2960, 1770, 1725, 1620, 1600, 1500, 1480, 1440, 1405, 1170, 1140, 1080, 980, 825, 755; MS (m/z) 309 [(M+H)+], 331 [(M+Na)+].
Reaction SMILES: [CH3:1][SiH:2]([CH3:10])[N:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[CH:4]([N:3]1[CH2:7][CH2:8][CH2:9][Si:2]1([CH3:10])[CH3:1])=[CH:5][CH3:6]
Reactant: C=CCN(CC=C)[SiH](C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC=CN1CCC[Si]1(C)C
Temperature: 80 °C
Yield: 98 %

Procedure:
Into a glass tube with an outside diameter of 10 mm and a length of 10 cm were introduced 2 mg RhCl(PPh3)3 and 2 mL of a mixture of 1 part N-dimethylsilyldiallylamine and 3 parts benzene, and the tube was sealed. After heating this for 17 hours at 80° C., The conversion was 100 weight % and 1-propenyl-2,2-dimethyl-1-aza-2-silacyclopentane was obtained in a yield of 98%. No production of 1-allyl-2,2-dimethyl-1-aza-2-silacyclopentane was observed.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>O1CCCC1.O>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:31]([C:32]5[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=5)=[O:38])[CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCNCC4)n3)cn2)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine (76 mg, 0.25 mmol) in tetrahydrofuran (4 mL) was added triethylamine (51 mg, 0.50 mmol) followed by nicotinoyl chloride (49 mg, 0.27 mmol) and the reaction mixture was stirred for 1 hour at 0° C. then allowed to warm to room temperature. The reaction was diluted with water and the organic material extracted three times with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude solid was chromatographed on silica (4 g) and eluted with ethanol-ethyl acetate to give the title compound as a solid; melting point 234° C.; Rf 0.31 with 0.5/10/40/50 acetic acid-isopropanol-hexane-dichloromethane; MS (ESI+) m/z 411 (M+1); H-PGDS FPBA IC50: 0.45 μM.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][CH2:18][C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)CNc1ncccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-Chloro-3-nitropyridine (5 g, 31.5 mmol) was dissolved in EtOH (125 ml), added potassium carbonate (4.35 g, 31.5 mmol) and to this mixture glycine (4.73 g, 6.3 mmol) in 25 ml water was added and refluxed for overnight. The reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound quantitatively as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7]C)=O.[CH2:13]([Mg]Br)[CH3:14].[CH2:17]1COC[CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([OH:7])([CH2:13][CH3:14])[CH2:17][CH3:18])[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Product: CCC(O)(CC)c1ccc(O)c(Cl)c1
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of methyl 3-chloro-4-hydroxybenzoate (25.0 g, 133 mmol) in THF (250 mL) is added dropwise 1.0 M ethylmagnesium bromide in THF (442 mL, 442 mmol) so as to maintain the temperature below 27° C. The resulting brownish grey solution is allowed to stir for 72 h during which time a cream-colored gelatinous precipitate is formed. The reaction mixture is cooled in an ice bath and quenched with 1 mL portions of sat. ammonium chloride solution until evolution of ethane subsides. Additional NH4Cl solution is added (to a total of 50 mL) and the resulting mixture is concentrated to remove most of the THF. The resulting residue is distributed into water and ether and filtered through diatomaceous earth to break the partial emulsion that forms. The organic layer is washed 3 times with sat. NaCl, dried over anhydrous magnesium sulfate and concentrated under vacuum to give the title compound (28.6 g, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[C:29]([Cl:30])=[CH:28][C:12]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][C@H:17]2[O:26][CH3:27])=[O:14])=[C:11](OC)[CH:10]=1.[C:33](=O)([O-])[O-:34].[Na+].[Na+]>CN(C)C(=O)C>[NH2:8][CH:9]1[C:29]([Cl:30])([O:34][CH3:33])[CH:28]=[C:12]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:18][C@H:17]2[O:26][CH3:27])=[O:14])[CH:11]=[CH:10]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Reactant: Clc1ncccn1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CO[C@@H]1CN(CCCNc2ncccn2)CC[C@@H]1NC(=O)C1=CC(Cl)(OC)C(N)C=C1
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 35 %

Procedure:
A mixture of 1.17 parts of 2-chloropyrimidine, 5.56 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 2.7 parts of N,N-dimethylacetamide was stirred for 6.5 hours at 90° C. After cooling, a sodium carbonate solution was added. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.4 parts (35%) of cis-4-amino-5-chloro-5-methoxy-N-[3-methoxy-1-[3-(2-pyrimidinylamino)propyl]-4-piperidinyl]benzamide; mp. 158.5° C. (compound 36).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)=[O:4].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[OH:15])=[O:21]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=O)c(O)ccc2c1
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
202.0 g (1.0 mol) of 6-methoxycarbonyl-β-naphthol were suspended in 1120 ml of 90%-strength acetic acid, nitrosated with 182 g (1.05 mol) of 40%-strength sodium nitrite solution at 0°-5° C. in the course of 2.5 hours and then stirring was continued at room temperature for 45 minutes. The suspension obtained was made up to 3 l with water, the solid was filtered off by suction and washed with water until neutral. After drying, 228.1 g (99.7%) of crude 1-nitroso-6-methoxycarbonyl-β-naphthol were obtained.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]([O:10][CH3:11])(=[O:9])C=C.C1N2[CH2:18][CH2:19]N(CC2)C1>>[CH3:11][O:10][C:6](=[O:9])[C:18](=[CH2:19])[CH:1]([OH:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: C=CC(=O)OC
Reactant: C1CN2CCN1CC2
Product: C=C(C(=O)OC)C(O)CCC
Yield: 305.6 %

Procedure:
A mixture of butanol (72.11 g, 1,000 mmol), methyl acrylate (129.14 g, 1,500 mmol) and DABCO (22.44 g, 200 mmol) is allowed to react at room temperature under N2 for 7 days. The reaction mixture is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills. The residue colorless liquid is dissolved in toluene (800 mL) and washed sequentially with 2 N HCl acid (250 mL), water (250 mL), saturated aq. sodium bicarbonate solution (120 mL) and water (150 mL). The toluene layer is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills to afford 3-hydroxy-2-methylenehexanoic acid methyl ester (96.7 g, yield: 61.1%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]([CH3:17])[C:4]=1[CH:5]=O.[CH3:18][C:19]([CH3:21])=[O:20].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:18][C:19](=[O:20])[CH3:21])=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: CC(C)=O
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)c(C=CC(C)=O)c(OC)c(OC)c1OC
Yield: 59.8 %

Procedure:
To a solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (1.56 g, 6.5 mmol) and acetone (1.13 g, 19.5 mmol) in methanol (15 ml) was added 28% methanolic sodium methoxide (1.88 g). The mixture was refluxed for 1.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column elution being carried out with isopropyl ether. The fractions containing the desired compound were concentrated to give 1,2,3,4-tetramethoxy-5-methyl-6-(3-oxo-1-butenyl)benzene (Compound 21, 1.09 g, 60% Oily substance) δ2.28 (3H), 2.36 (3H), 3.77 (3H), 3.79 (3H), 3.89 (3H), 3.95 (3H), 6.70 (1H), 7.57 (1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[I-:11].[K+].II.[NH:15]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[SH:21]>CO.O>[IH:11].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:21][C:16]1[NH:17][CH2:18][CH2:19][CH2:20][N:15]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [I-]
Reactant: SC1=NCCCN1
Reactant: Cc1cc2ccccc2[nH]1
Agent: II
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c2ccccc2c1SC1=NCCCN1
Product: I
Reaction time: 2 h

Procedure:
A solution of 19.65 g of 2-methylindole in 250 ml of methanol is added to a well-stirred solution of 75 g of potassium iodide and 38 g of iodine in 225 ml of water at room temperature. This mixture is further treated with a solution of 17.4 g of 1,4,5,6-tetrahydro-2-pyrimidinethiol in 350 ml of warm methanol, stirred for 2 hours and worked up in the manner described under Example 1 to yield 2-methyl-3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 242° after recrystallization from a mixture of methanol and ethyl acetate.