Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H][H].[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][N:17]=2)[CH2:12][CH2:11]1)#[N:9]>>[CH:1]1([CH2:4][O:5][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[S:18][N:17]=3)[CH2:12][CH2:11]2)=[NH:9])[CH2:3][CH2:2]1
Reactant: N#CN1CCC(c2nsc3ccccc23)CC1
Reactant: OCC1CC1
Reactant: [H][H]
Product: N=C(OCC1CC1)N1CCC(c2nsc3ccccc23)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 15 ml of cyclopropylcarbinol was added 0.05 g of Na metal. After the evolution of hydrogen gas ceased, 3-(1-cyano-4-piperidinyl)-1,2-benzisothiazole (4.0 g, 0.016 mole) was added. The temperature was raised to 60° C. to obtain a solution. Heat was removed and the reaction mixture was stirred at ambient temperature for 16 hours. Dry ice was added to the reaction mixture to destroy the excess alkoxide and the mixture was poured into water. The aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with water and dried over MgSO4, and the solvent was removed in vacuo to leave an oil. The oil was triturated with hexane to yield 4.0 g of a solid. The solid was recrystallized twice from isopropyl ether to yield 2.4 g (46.3%) of the imidate as a solid, m.p. 85°-87°.
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH:5]([NH:12][C:13](=O)[CH2:14][O:15][CH3:16])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([C:4]2[O:18][C:13]([CH2:14][O:15][CH3:16])=[N:12][C:5]=2[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(NC(=O)COC)C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(COC)oc1C1CC1
Temperature: 0 °C
Yield: 96 %

Procedure:
Ethyl 4-Cyclopropyl-3-[(methoxyacetyl)amino]-4-oxobutanoate (Preparation 121, 25.7 g, 0.1 mol) was dissolved in dry DMF (170 mL). POCl3 (46 g, 0.3 mol) was poured into this solution at 5-15° C., and the mixture was kept this temperature for 60 minutes. The resulting solution was slowly poured in portions into crushed ice (700 g) and stirred until a homogeneous solution was obtained. The solution was neutralized with a 20% aqueous K2CO3 solution to pH 7-8. The product was extracted with ethyl acetate. The organic extract was washed with brine and concentrated in vacuo to give a dark-brown liquid, which was purified by silica gel column chromatography eluting with EtOAc:Hexane 1:1 to afford the title compound as a colourless liquid (96%). Taken directly on to the next step.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3][C:2]1=[S:11].Cl[CH2:13][C:14](O)=[O:15].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[S:11]1[C:2]2=[N:1][C:10]3[C:5]([CH2:4][N:3]2[C:14](=[O:15])[CH2:13]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: O=C(O)CCl
Reactant: S=C1NCc2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC2=Nc3ccccc3CN12
Temperature: 90 °C

Procedure:
A mixture of 1.0 g (0.006 mol) 3,4-dihydro-2(1H)-quinazolinethione (compound II), 0.57 g (0.006 mol) chloroacetic acid, and 0.54 g (0.0065 mol) sodium bicarbonate is mixed in 31.25 ml water, and heated overnight at 90° C. Then, 12.5 ml of dimethylformamide is added, and the reaction mixture is refluxed for 61/2 hours. After cooling, 5H-thiazolo[2,3-b]quinazolin-3(2H)-one, as the precipitated solid, is filtered off and recrystallized from anhydrous ethanol. Replacement of 3,4-dihydro-2(1H)-quinazolinethione by a derivative thereof in which a nuclear hydrogen of the benzene ring has been substituted with lower alkyl, alkoxy, halogen, trifluoromethyl, NO2 or NH2, results in the corresponding derivative of 5H-thiazolo[2,3-b]quinazolin-3(2H)-one.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:34](N)[CH2:35][NH2:36]>ClC1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]3[NH:36][CH2:35][CH2:34][N:21]=3)=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C#N)CC1
Reactant: NCCN
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C2=NCCN2)CC1

Procedure:
To a solution of zinc chloride (28 mg, 0.149 mmol) and 4-[5-cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (1 g, 2.09 mmol) in chlorobenzene (15 mL), ethane-1,2-diamine (0.100 mL, 1.463 mmol) was added. The mixture was heated under reflux for 24 h. LCMS indicated desired product. The crude was concentrated under vacuo and purified by HPLC to afford compound A92 as a yellow solid (303 mg, 23%). 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, 6H), 1.68-1.77 (m, 2H), 2.05-2.09 (m, 2H), 3.07 (s, 3H), 3.16-3.23 (m, 2H), 3.84-3.92 (m, 2H), 4.07 (s, 4H), 4.87-4.92 (m, 1H), 5.42-5.47 (m, 1H), 7.50-7.62 (m, 2H), 7.79-7.83 (m, 1H), 8.35 (s, 1H). Exact mass calculated for C23H29FN6O5S 520.19, found 521.5 (MH+).
Reaction SMILES: C(O[SiH](O[CH2:9][CH3:10])OCC)C.[C:11]1([C:13](=[CH:15][C:16](=[C:18]([CH:20]=1)C)C)C)[CH3:12]>>[C:11]1([CH:12]([C:10]2[CH:9]=[CH:18][CH:20]=[CH:11][CH:12]=2)[CH2:13][CH2:15][CH3:16])[CH:20]=[CH:18][CH:16]=[CH:15][CH:13]=1
Reactant: Cc1cc(C)c(C)cc1C
Reactant: CCO[SiH](OCC)OCC
Product: CCCC(c1ccccc1)c1ccccc1

Procedure:
Triethoxisilane (compound 2, 0.6 mmol) instead of pentamethyldisiloxane was used for the same reaction to Example 14A. 1H-NMR analysis with durene as an internal standard material without isolation of products showed that (4,4-diphenylbuthyl) triethoxysilane (compound 3) was produced with the yield of 85%, and 1,1-diphenylbutane (compound 4) was produced with the yield of 6%.
Reaction SMILES: [CH3:1][C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O.C1(C)C=CC=CC=1.[CH3:83][NH:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1.[CH2:91]([N:98]1[C:102](=[O:103])[CH2:101][S:100][C:99]1=[S:104])[C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1>>[CH2:91]([N:98]1[C:102](=[O:103])[C:101](=[CH:83][N:84]([C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[CH3:1])[S:100][C:99]1=[S:104])[C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C1CSC(=S)N1Cc1ccccc1
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccccc1
Yield: 39 %

Procedure:
To a mixture of TMOF-toluene (1:1, 6 mL, anhyd) was added N-methylaniline (0.33 mL, 3.0 mmol) and 3-benzylrhodanine (0.67 g, 3.0 mmol). After heating at reflux for 2 h, the reaction mixture was cooled, concentrated and chromatographed (silica gel, 0:100 to 40:60 EtOAc-Hex) to yield the title product (0.40 g, 39%) as a yellow solid. 1H-NMR (CDCl3): δ 7.79 (1H, s), 7.34-7.47 (5H, m), 7.17-7.31 (5H, m), 5.25 (2H, s), 3.54 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (0.63 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.35 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.43 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (0.91 g). LC/MS m/z 360 [M+H]+.
Reaction SMILES: N1C=CC=C1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.C([O-])([O-])=[O:31].[K+].[K+].Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CC(C)=O>[OH:31][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[C:20]2[CH2:25][C:24]([CH3:26])([CH3:27])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][CH:18]=2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc[nH]3)cc2)CC(C)(C)C1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 34.7 %

Procedure:
The O-alkylation procedure described for 190 was employed. To a suspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (19) (0.500 g, 1.74 mmol), K2CO3 (0.257 g, 1.86 mmol), and acetone (75 mL) was added ethyl 2-bromo-2-methylpropanoate (0.33 mL, 2.3 mmol) at RT. The reaction mixture was refluxed for 48 h, and filtered. The filtrate was concentrated and purified to afford 0.272 g (40%) of compound 227 as a white foam. In addition, 0.200 g of unreacted SM was recovered. 1H NMR (300 MHz, CDCl3): δ7.04 (d, J=1.8 Hz, 2H), 7.01 (d, J=1.8 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.77 (d, J=2.7 Hz, 2H), 6.74 (d, J=2.4 Hz, 2H), 4.75 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.96 (d, J=6.9 Hz, 4H), 1.60 (s, 6H), 1.29 (s, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.934 (s, 6H), 0.92 (s, 6H). LCMS (ESI): m/z 449 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CC=CC=1.[CH2:16]([O:32][C:33]1[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](Cl)=[O:40])=[CH:35][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:16]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[O:40])=[CH:42][CH:43]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccccc1CO
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CO)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 1.36 g of 0-aminobenzyl alcohol and 2.69 g of pyridine in 60 ml of methylene chloride is added dropwise with stirring over 40 minutes a solution of 3.5 g of 4-hexadecyloxyphenoxyacetyl chloride in 40 ml of methylene chloride. Stirring is continued at room temperature for 4 hours. The mixture is diluted with chloroform and heated to dissolve the solids, washed with water and dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride to give 3.9 g of the desired product as a white solid, m.p. 128°-131° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4](Cl)[N:3]=1.[Cl:15][C:16]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:17]=1[CH2:18][N:19]1[CH:23]=[CH:22][C:21](=[O:24])[NH:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:24][C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C:17]3[C:16]([Cl:15])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[N:20]=2)[N:3]=1
Reactant: O=c1ccn(Cc2c(Cl)cccc2Cl)[nH]1
Reactant: COC(=O)Cc1c(C)nc(C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)Cc1c(C)nc(C)nc1Oc1ccn(Cc2c(Cl)cccc2Cl)n1

Procedure:
A mixture of methyl (2,4-dimethyl-6-chloro-5-pyrimidinyl)-acetate (0.5 g, 23 mmol), 1-(2,6-dichlorobenzyl)-1H-pyrazol-3-on (5.80 g, 23 mmol) and potassium carbonate (10.0 g, 70 mmol) in dimethylformamide (30 ml) is heated at +130° C. for 2 hours. Addition of water, extraction with ether and drying gives the intermediate methyl 2-[2,4-dimethyl-6-(1-(2,6-dichlorobenzyl)-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-acetate as a yellow oil.
Reaction SMILES: O[CH:2]([CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.CCCCCC.CC[O:45]CC>>[C:21]1([S:27]([O:29][CH:3]([CH2:2][CH2:18][CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:45])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOCC
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCC(O)CCCCCCCCSCCC(=O)OC
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCC(CCCCCCCSCCC(=O)OC)OS(=O)(=O)c1ccccc1
Yield: 83 %

Procedure:
Compound 7 (0.83 g, 2.7 mmol) was caused to react with benzenesulfonylchloride (0.45 ml, 3.5 mmol) and pyridine (3.5 mmol) in CHCl2 (20 mL) at 5° C. for 20 hr. The mixture was ice-diluted HCl, and the organic layer separated, dried (MgSO4 and evaporated under reduced pressure. The product 8 (1.0 g. 83% yield) was isolated as an oil by column chromatography (hexane/ether 1:1). TLC (hexane/ether 1:1) Rf=0.5. 1H-NMR δ0.82 (t, 3H, C(16)H2), 1.4 (m, 18H, CH2), 2.52 (t, 2H, C(2)H2), 2.62 (t, 2H, C(5)H2), 2.78 (t, 2H, C(3)H23.70 (s, 3H, —COO—CH3), 4.60 (m, 1H, C(13)H), 7.7 (m, 5H, aryl).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].CO.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2nc(C(C)C)[nH]c2c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(C(C)C)[nH]c2c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Isopropyl-5-methoxybenzimidazole (50 g) was dissolved in 150 mL TFA and to the mixture was added 5 mL 90% nitric acid. The reaction was stirred overnight, and the solvents removed in vacuo and the residue neutralized to pH 7 with saturated aqueous sodium bicarbonate. The residue was extracted with ethyl acetate (4×100 mL). The combined ethyl acetate fractions were dried over sodium sulfate and concentrated to give a dark residue. Chromatography (3% methanol/methylene chloride) gave 2-isopropyl-4-nitro-5-methoxybenzimidazole as a yellow solid, 24 g. Also obtained was 25 g of 2-isopropyl-5-nitro-6-methoxybenzimidazole.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[S:29][C:28]2=[N:30][CH:31]=[C:32]([C:33](O)=[O:34])[N:27]2[CH:26]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:27]3[C:28]([S:29][C:25]([CH3:24])=[CH:26]3)=[N:30][CH:31]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cn2c(C(=O)O)cnc2s1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sc(C)cn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=491.9.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]3([O:21][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:17](=[S:20])[NH:18][CH3:19])[CH2:8]3.[I:24]C.[CH2:26](O)C>CCOCC>[IH:24].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]3([O:21][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:17](=[SH:20][CH3:26])[NH:18][CH3:19])[CH2:8]3
Reactant: CI
Reactant: CCO
Reactant: CNC(=S)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Solvent: CCOCC
Product: CNC(=[SH]C)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Product: I
Yield: 99 %

Procedure:
A solution of 6-chloro-2'-(N-methylthiocarbamyl)spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (12.0 g) and iodomethane (7.4 g) methanol (150 ml) and ethanol (100 ml) is heated under reflux for four hours. Removal of solvents in vacuo yields a solid which, upon trituration with ether, yields product as a solid (16.4 g, 99%). An analytical sample is recrystallized from ethyl acetate/methanol to yield a white solid, 181°-182° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Sn](CCCC)(CCCC)CCCC.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:33]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1(C)C(C)=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:33]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cncc(-c2c(F)cccc2F)c1
Yield: 81 %

Procedure:
A mixture of (2,6-difluorophenyl)tributyltin (1.18 g, 2.9 mol), ethyl 5-bromonicotinate (0.69 g, 3 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g) in xylene (10 mL) was heated under reflux for 24 h, then cooled, filtered and evaporated. The residue was chromatographed on silica gel eluted with 20% ethyl acetate/petrol to give the title compound (0.64 g, 84%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[C:12]1(=O)[C:21]2[C:16]3[C:17](=[CH:22][CH:23]=[CH:24][C:15]=3[C:14](=[O:25])[O:13]1)[CH:18]=[CH:19][CH:20]=2>S(=O)(=O)(O)O>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][C:9]=1[CH3:10])[C:12]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]3[C:16]=1[C:15]([C:14]([OH:13])=[O:25])=[CH:24][CH:23]=[CH:22]3)=[C:7]1[C:6](=[CH:5][C:4](=[N:3][CH2:1][CH3:2])[C:9]([CH3:10])=[CH:8]1)[O:11]2)[CH3:2]
Reactant: CCNc1cc(O)ccc1C
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: O=S(=O)(O)O
Product: CCN=c1cc2oc3cc(NCC)c(C)cc3c(-c3cccc4cccc(C(=O)O)c34)c-2cc1C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
3-Ethylamino-4-methyl-phenol (0.3 g, 2 mmol) and benzo[de]isochromene-1,3-dione (0.2 g, 1 mmol) in sulfuric acid (3 ml) was heated to 150° C. over a period of 6 h. The reaction mixture was pouring into crushed ice, allowed to stand over a period of 1 h and the precipitate was filtered. The filtrate was neutralized with concentrated ammonium hydroxide and concentrated to give a dark purple residue. Purification via preparatory layer chromatography (PLC, 1 mm silica gel, 9/1 DCM: MeOH, 2% AcOH) gave the title compound (50 mg). ABS λmax=527 nm (EtOH).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10](O)[C:11]1[C:16]([F:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>FC(F)(F)C(O)=O>[F:17][C:16]1[C:11]([CH:10]2[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:1][NH:8][CH2:9]2)=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(F)c(C(O)CNCc2ccccc2)cc1OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3ccccc32)cc1OC
Reaction time: 1.17 h
Yield: 100.3 %

Procedure:
α-[(benzylamino)methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (1.25 g) was dissolved in 8.75 ml of trifluoroacetic acid, and after adding thereto 0.37 ml of conc. sulfuric acid under ice-cooling, the mixture was stirred for 70 minutes. Then, 1.07 g of sodium acetate was added to the mixture, and the reaction mixture was concentrated. To the residue, was added chloroform and water, and the mixture was basified by addition of conc. aqueous ammonia under ice-cooling. By a separating procedure, the chloroform layer was collected, washed with saturated aquous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation, giving 1.18 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as a syrupy matter.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[S:20]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:19]([Cl:21])=[S:20])=[O:5])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCCCN1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCCN1C(=S)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
With the temperature maintained at 30° or below, a mixture of N-ethoxycarbonylhexahydropyridazine (1.5 g, 9.49 mmol) and triethylamine (1.0 g, 9.49 mmol) in 8 ml of benzene is added dropwise to a stirring solution of thiophosgene (1.1 g, 9.49 mmol) in 10 ml of benzene. The reaction is stirred at RT for 4 hours, and is then diluted with benzene to 50 ml, quickly washed with water and with brine, dried and stripped to give N-ethoxycarbonyl-N'-chlorothiocarbonylhexahydropyridazine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].CN1CCOCC1.[C:23]1(=[O:42])[N:27]([C@@H:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29](O)=[O:30])[C:26](=[O:37])[C:25]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:24]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:26]1(=[O:37])[N:27]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29]([NH:7][C@@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:30])[C:23](=[O:42])[C:24]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:25]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](Cc1ccccc1)NC(=O)C(CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of L-phenylalanine ethyl ester hydrochloride salt (998 mg., 4.3 mmol) in dimethylformamide (10 mL.) was added with 4-methylmorpholine (575 μl, 529 mg., 5.2 mmol.). After stirring at room temperature for 5 minutes, the solution was cooled to 0° C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (1:1--acetone:hexanes) Rf =0.30.
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:14].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[ClH:14].[C:1]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [Al+3]
Solvent: c1ccccc1
Product: Cl
Product: c1ccc(C2(c3ccccc3)CCNCC2)cc1

Procedure:
When proceeding as described in Example 1, but replacing 1-methyl-4-hydroxy-4-phenylpiperidine (used as starting material in said example) by 4-phenyl-4-hydroxypiperidine and reacting 17.8 g. thereof with benzene in the presence of aluminum chloride, 12.0 g. of 4,4-diphenylpiperidine hydrochloride are obtained. Said hydrochloride melts at 300° C. (with decomposition) after recrystallization from a mixture of ethanol and isopropanol. The 4,4-diphenylpiperidine base melts at 70° to 72° C.