Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:24]([N:4]1[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=[C:3]1[S:2][CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2n1Cc1ccccc1
Yield: 54.7 %

Procedure:
A solution of 1.0 g (3.10 mmol) of 2-methylsulphanyl-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 15 ml of dimethylformamide was combined with 547 mg (3.20 mmol) of benzylbromide and then with 442 mg (3.20 mmol) of potassium carbonate and stirred overnight at ambient temperature. Then it was diluted with approx. 40 ml of water and extracted three times with 15 ml of ethyl acetate. The organic extracts were washed with water, dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 10–20% ethyl acetate).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12](=[O:23])[C:13]3[C:18]([C:19](=[O:22])[C:20]=2[OH:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>S(=O)(=O)(O)O>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[C:12](=[O:23])[C:13]3[C:18]([C:19](=[O:22])[C:20]=2[OH:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(C2=C(O)C(=O)c3ccccc3C2=O)CC1
Agent: O=S(=O)(O)O
Product: CC(C)(C)[C@H]1CC[C@@H](C2=C(O)C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C

Procedure:
An approximately 1:1 cis/trans mixture of 2-(4'-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquine (see Example 1) (10 g) was dissolved in concentrated sulphuric acid (100 ml) and the solution maintained at various temperatures for various periods of times as shown below. At the end of the reaction the reaction mixture was cooled and poured dropwise into ice/water to provide crude product which was purified by recrystallisation as previously described and/or column chromatography. The isomers ratios of the product were determined by NMR, GLC.; the results shown below.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)OCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred solution of 2-aminothiazole (AA1-A, 3.0 g, 30.0 mmol) and triethylamine (6.30 mL, 45.0 mmol) at 0° C. was added benzyl chloroformate (5 mL, 36 mmol). The reaction was stirred at RT O/N. The reaction mixture was washed with a saturated aqueous solution of NaHCO3, then water and concentrated to dryness under reduced pressure. The resulting yellow solid was crystallized from ethanol to afford AA1-2 in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O:23][C:24](=[O:36])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:34][C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[CH2:26][CH2:25][C:24]([OH:36])=[O:23])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Reactant: COC(=O)CCc1cc(F)ccc1CBr
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(F)cc2CCC(=O)O)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 3-(2-bromomethyl-5-fluoro-phenyl)-propionic acid methyl ester analogous to Example 2c and then saponified to give 3-(2-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-5-fluoro-phenyl)-propionic acid. MS: m/e=509.3 (MH−).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)C(F)(F)F)[C@@H:12]1[CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH2:16])[C@@H:12]1[CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]([CH3:25])[CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(C)C)[C@H]1[C@H](NC(=O)C(F)(F)F)CCN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C(C)C)[C@H]1[C@H](N)CCN1C(=O)OCc1ccccc1
Yield: 72 %

Procedure:
Intermediate 6 (31 g), potassium carbonate (71 g), water (930 ml) and ethanol (930 ml) were warmed at 60° C. for 3 h. The ethanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (3×300 ml). The combined extracts were washed with brine and dried (MgSO4) and concentrated in vacuo to give the title compound as a brown oil (17.5 g).
Reaction SMILES: O.Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].P(Cl)(C(C)(C)C)C(C)(C)C.C(Cl)Cl>[C:11]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccccc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
In the drybox, 110 mg (0.609 mmol) of (Me3C)2P—Cl, 67 mg (0.299 mmol) of Pd(OAc)2 and 3.0 mL of CH2Cl2 were loaded into a reactor (10 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 4 h before 60 mg (3.3 mmol) of H2O was added. The mixture above was stirred at room temperature for 12 h. After removal of solvent and excess H2O, the residue was dissolved in 15.0 mL of 1,4-dioxane, and transferred into a reactor (100 mL). Next, 2-chloroanisole (1.43 g, 10.0 mm), C6H5B(OH)2 (1.83 g, 15.0 mm) and CsF (4.56 mg, 30.0 mmol) were added into the mixture above. After the mixture was refluxed for 42 h, the reaction mixture was then cooled to room temperature, quenched with 50 mL of H2O, and extracted with 300 mL of diethyl ether. The organic extracts were washed with H2O (2×50 mL), brine (50 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.81 g (98% yield) of 2-phenylanisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.85 (d, J=7.05 Hz, 2H), 7.67 (m, 2H), 7.60 (m, 3H), 7.32 (m, 1H), 7.22 (m, 1H), 4.01 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ156.4, 138.5, 130.7, 130.6, 129.4, 128.5, 127.8, 126.7, 120.7, 111.2, 55.3 ppm. HRMS Calcd for C13H12O: 185.0966. Found 185.0965. Anal. Calcd for C13H12O: C, 84.75; H, 6.57; O, 8.68. Found: C, 84.62; H, 6.65; O, 8.58.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH2:22][OH:23]>CN(C)C=O>[OH:23][CH2:22][CH2:21][N:16]1[C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2nc(-c2ccccc2)n1CCO
Reaction time: 1 h

Procedure:
To a stirred mixture of 18 parts of 2-phenyl-4(3H)-quinazolinone and 225 parts of N,N-dimethylformamide are added portionwise at room temperature 3.2 parts of sodium hydride dispersion 60% (exothermic reaction: the temperature rises to 34° C.). After the addition is complete, the whole is stirred for 10 minutes whereafter 12.4 parts of 2-bromoethanol are added dropwise (slightly exothermic). Upon completion, stirring is continued first for one hour at room temperature, then for 2 hours at 80° C. and further overnight at room temperature. The reaction mixture is cooled, poured onto water and the solid product is sucked off. It is washed with water and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 15 parts of 3-(2-hydroxyethyl)-2-phenyl-4(3H)-quinazolinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCN
Solvent: c1ccccc1
Product: CCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.50 g, 4.12 mmol), butylamine (0.420 g, 5.74 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-butyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.11 g, 61.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5]>C(O)C.[Ni]>[NH2:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(N)c1
Yield: 88.7 %

Procedure:
0.19 g (0.000537 mol) of 1-benzyl-piperidin-4-yl 2-amino-4-nitro-benzoate was dissolved in 16 ml of ethanol, treated with 0.115 g of Raney-Nickel and hydrogenated under normal pressure. The catalyst was filtered off, the solvent was removed on a rotary evaporator and the residue was chromatoraphed on silica gel with ethyl acetate/hexane (1:1→1:1) as the eluent. 0.155 g (89%) of 1-benzyl-piperidin-4-yl 2,4-diamino-benzoate was obtained as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]([CH2:13][OH:14])([CH2:11][OH:12])[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:19])=O.COC(OC)(C)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([C:7]1([C:8](=[O:10])[CH3:9])[CH2:11][O:12][C:17]([CH3:19])([CH3:16])[O:14][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(CO)(CO)C(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC(=O)C1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 2,2-bis-hydroxymethyl-3-oxo-butyric acid tert-butyl ester (8.67 g, 40 mmol), acetone (30 mL, 400 mmol), 2,2-dimethoxypropane (41.6 g, 50 mL, 400 mmol) and 4-toluenesulfonic acid hydrate (152 mg, 0.8 mmol) was stirred at room temperature for 18 h. The solvent was partially evaporated to a volume of ˜20 mL. Saturated sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine. The organic layer was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 4:1 to afford the title compound (7.82 g, 75%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.39 (s, 3H), 1.44 (s, 3H), 1.48 (s, 9H), 2.32 (s, 3H), 6.36 (ABq, ΔδAB=0.05, JAB=11.8 Hz, 4H). LCMS (m/z) 281.2 [M+Na], Tr=2.44 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26](Cl)=[O:27]>>[CH3:24][O:25][C:26](=[O:27])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OC)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid methyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and methylchloroformate (89 μl, 1.16 mmol). The title compound was obtained as white powder (200 mg, 56%).
Reaction SMILES: N1C=CC=CC=1CO.BrC1C=NC=CC=1.COC1C=C(C(C2C=NC=CC=2)O)C=CC=1OC.C[O:35][C:36]1[CH:37]=[C:38]([C:44]2[C:49]([C:50]([C:52]3[C:53]([C:58]4[CH:63]=[CH:62][C:61]([O:64]C)=[C:60]([O:66]C)[CH:59]=4)=[N:54][CH:55]=[CH:56][CH:57]=3)=[O:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:39]=[CH:40][C:41]=1[O:42]C.Br>>[OH:66][C:60]1[CH:59]=[C:58]([C:53]2[C:52]([C:50]([C:49]3[C:44]([C:38]4[CH:39]=[CH:40][C:41]([OH:42])=[C:36]([OH:35])[CH:37]=4)=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:51])=[CH:57][CH:56]=[CH:55][N:54]=2)[CH:63]=[CH:62][C:61]=1[OH:64]
Reactant: COc1ccc(-c2ncccc2C(=O)c2cccnc2-c2ccc(OC)c(OC)c2)cc1OC
Agent: Br
Agent: COc1ccc(C(O)c2cccnc2)cc1OC
Agent: OCc1ccccn1
Solvent: Brc1cccnc1
Product: O=C(c1cccnc1-c1ccc(O)c(O)c1)c1cccnc1-c1ccc(O)c(O)c1

Procedure:
3,4-Dimethoxyphenyl-3-pyridyl carbinol was obtained as an oil as described for the preceding 2-pyridyl carbinol of Example 40 except that 3-bromopyridine is used in place of 2-bromopyridine. This carbinol was converted to 3,4-dimethoxyphenyl-3-pyridyl ketone, mp 76°-78° C and reacted with hydrobromic acid to give 3,4-dihydroxyphenyl-3-pyridyl ketone, mp 182°-184° Crown ether formation as described in Example 40 gave 1-(2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16 hexaoxacyclooctadecin-18-yl)-1-(3-pyridyl)-methanone, mp 98°-100° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:11][C:5]=2[N:4]=1.[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:13]([NH:12][C:10]4[CH:9]=[CH:8][C:6]5[NH:7][C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][C:5]=5[CH:11]=4)=[O:20])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc2[nH]c(C(F)(F)F)nc2c1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]c(C(F)(F)F)nc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 32.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl [2-(trifluoromethyl)-1H-benzimidazol-5-yl]carbamate (278 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.811 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 115 mg (32.8%) of the desired product as a solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][C:5]1[S:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[C:10]#[N:11]>O1CCOCC1>[CH3:3][S:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CCOC(=O)c1cc(C#N)c(SC)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1sccc1C#N
Temperature: 200 °C
Reaction time: 2 h

Procedure:
To a solution of 4.36 g of 2-methylthio-3-cyano-5-ethoxycarbonylthiophene, obtained according to Example IV (a), in 40 ml of dioxane, is added while stirring 40 ml of 2N NaOH. After stirring for two hours the reaction mixture is acidified with 45 ml 2N Hcl. The precipitated 5-carboxythiophene compound is sucked off, washed with water and recrystallized from acetonitrile; yield 3.01 g; melting point 230°-234° C. This 5-carboxythiophene compound in an amount of 1.99 g together with 4 ml of quinoline and 0.4 g of Cu-powder is heated on 200° C. during approx. 15 minutes. After cooling down, diethylether, water and 20 ml 2N Hcl are added. The ether phase is separated off, washed with water, dried, decolorized with charcoal, filtered and evaporated. 2-Methylthio-3-cyanothiophene is obtained in a yield of 0.92 g as an oil; Rf (CH2Cl2)=0.45. The reaction is repeated with larger quantities. The last product in an amount of 6.98 g is added dropwise to a mixture of 7.1 ml of ClSO3H and 8.9 g of Pcl5 under stirring and cooling to below 20° C. After stirring for half an hour at room temperature, the mixture is poured on ice. The formed precipitate is sucked off, washed with water and dissolved in methylene chloride. After drying, decolorizing with charcoal, filtration, adding diisopropylether and evaporating methylene chloride, the desired 2-methylthio-3-cyano-5-chlorosulphonylthiophene precipitates in an amount of 7.60 g; melting point 112°-115° C. The above chlorosulphonyl compound is converted to the corresponding methylsulphonyl compound via the corresponding sodium sulphinate by adding 7.50 g to 7.6 g of Na2SO3 and 10.1 g of NaHCO3 in 60 ml of water. While stirring the reaction mixture is warmed slowly up to 70° C. and stirred at 70° C. for half an hour. To the solution obtained 3.75 ml of methyl iodide is added; reflux for 5 hours. After evaporating the volatile components in vacuo, the formed precipitate is sucked off, washed with water and recrystallized from methanol. 2-Methylthio-3-cyano-5-methylsulphonylthiophene is obtained in a yield of 2.88 g; melting point 126°-128° C.
Reaction SMILES: NC[C@@H](C1C=CC(O)=C2C=1C=CC(=O)N2)O[Si](C(C)(C)C)(C)C.[N:24]([CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36]CC2C=CC=CC=2)=[C:32]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:31]=1)[OH:29])=[N+]=[N-]>>[NH2:24][CH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH:31]=1)[OH:29]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN)ccc1O

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 2, using Intermediate 8 as a substrate. ES/MS calcd. for C15H27NNaO3Si+ 320.2. Found m/z=320.2 (M+Na)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])C.CO.[OH-].[Na+]>C1COCC1>[Cl:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:12]([C:10]([NH:9][C:5]([CH3:8])([CH2:6][CH3:7])[C:4]([OH:31])=[O:3])=[O:11])[CH:21]=1
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A solution of 70 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester (see example 160, step b)) in 4 mL THF and 1 mL MeOH was treated with 4 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo. The residue was taken up in 6 ml of water and it was treated with 2 M hydrochloric acid to adjust the pH to 6-7, then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 32 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[N:10]\[S:11]([N:14]2[C:19]3([CH2:21][CH2:20]3)[CH2:18][N:17]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][S:11]([N:14]2[C:19]3([CH2:20][CH2:21]3)[CH2:18][N:17]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=N\S(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNS(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(NZ)—N-[(4-methoxyphenyl)methylene]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 49) was dissolved in MeOH, added NaBH4 (1 eq) and stirred at rt for 2 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 04048 mmol) in toluene 10 mL was added 4-(trifluoromethyl)benzaldehyde 84 (70.4 mg, 0.404 mmol). PTSA (153.9 mg, 0.809 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude 85 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 85 was eluted at 28% ethyl acetate in hexane to afford yellow coloured solid compound (E)-6-methoxy-5-morpholino-2-(4-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 85.