Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[F:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[F:13][C:6]1[CH:7]=[C:8]([F:12])[CH:9]=[C:10]([F:11])[C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1
Reactant: O=C(CCl)c1c(F)cc(F)cc1F
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2c(F)cc(F)cc2F)cs1
Yield: 97 %

Procedure:
A mixture of 2-chloro-1-(2,4,6-trifluorophenyl)ethanone (9.04 g, 43.5 mmol) and thiourea (3.51 g, 46.1 mmol) in 95% EtOH (50 mL) was heated at reflux overnight. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The solids were filtered and dried under vacuum to give 4-(2,4,6-trifluorophenyl)thiazol-2-amine (9.71 g) as pink-white solids in 97% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.26-7.22 (m, 2H), 7.09 (s, 2H), 6.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O=S(Cl)Cl.Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]=[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(Cc2ccccc2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=C(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 40.0 g (123 mmol) of 4-benzyl-4-hydroxy-piperidine-1-carboxylic acid benzyl ester in 250 ml CH2Cl2 were added 39.6 ml (492 mmol) pyridine and at 0° C. 17.8 ml (246 mmol) of SOCl2. The reaction mixture was stirred for 30 min. at 0° C. and then 250 ml of aqueous (2N) HCl were added. The aqueous phase was extracted twice with CH2Cl2 and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 36.3 g (118 mmol, 96%) of 4-benzyl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].[NH2:14][OH:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]([NH:14][OH:15])=[NH:6]
Reactant: NO
Reactant: CC(C)Oc1ccc(C#N)cc1Cl
Solvent: CCO
Product: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Temperature: 60 °C
Yield: 98.4 %

Procedure:
Into a round bottom flask was added 3-chloro-4-isopropoxy-benzonitrile (5.00 g, 25.6 mmol), hydroxylamine (50% by weight in water, 1.86 mL, 28.1 mmol) and ethanol (150 mL). The mixture was heated at about 60° C. overnight. Upon completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give 3-chloro-N-hydroxy-4-isopropoxy-benzamidine (5.76 g, 94%) as a light yellow solid.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11]>C(OCC)C.C(N(CC)CC)C>[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][S:11][C:2]1[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=1
Reactant: CCCCCC(C)(O)CS
Reactant: O=C1CCC2OC12
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCC(C)(O)CSC1=CCCC1=O
Yield: 69.3 %

Procedure:
2,3-Epoxycyclopentanone (1.47 g) and 2.0 g of 2-hydroxy-2-methylheptyl mercaptan were dissolved in 30 ml of diethyl ether, and 30 drops of triethylamine were added. They were reacted at room temperature for 2 hours. The solvent was distilled off from the reaction mixture to afford 4.01 g of a crude product. The crude product was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 2.07 g of 2-(2-hydroxy-2-methylheptylthio)cyclopent-2-en-1-one in a yield of 69%. The product had the following characteristics.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][C:19](=[O:26])[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)c1ccccc1

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 was acylated with benzoyl chloride following General Procedure K and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (34 mg) following General Procedure A to give 286. MS (Q1) 471 (M)+
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([S:16](C2C=CC=CC=2CC2C3C(=CC=C(F)C=3)N(CC(O)=O)C=2C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([S:16][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Product: O=Cc1ccc(SC2CCCCC2)cc1

Procedure:
4-Fluorobenzaldehyde was used as a starting material, otherwise this compound was prepared in a similar manner to Compound 1, following Procedure A.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[S:10][C:11]([CH2:14][OH:15])=[N:12][C:13]=3[C:4]=2[CH:3]=1.Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[S:10][C:11]([CH2:14][O:15][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: OCc1nc2c(s1)-c1ccccc1Sc1ccc(F)cc1-2
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOCc1nc2c(s1)-c1ccccc1Sc1ccc(F)cc1-2

Procedure:
By reacting the alcohol 80 (0.84 mmole) and 3-dimethylaminopropylchloride-hydrochloride (19 mmoles) an oily product was obtained.
Reaction SMILES: I[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)#[CH:14].C(N(CC)CC)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[N:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:12][C:3]3=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: Oc1ncc(C(F)(F)F)cc1I
Reactant: C#Cc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc2oc(-c3ccncc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
A mixture of 0.29 g of 3-iodo-5-(trifluoromethyl)pyridin-2-ol, 0.35 g of 4-ethynylpyridine, 20 mg of dichlorobis(triphenylphosphine)palladium(II), 0.30 g of triethylamine, 15 mg of copper(I) iodide and 5 ml of DMF was stirred under a nitrogen atmosphere at room temperature for 2 hours. To the reaction mixture were added water, then t-butyl methyl ether, and the mixture was filtered through Celite (registered trademark). The filtrate was separated, and the organic layer was dried over sodium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel preparative thin-layer chromatography to obtain 33 mg of 2-(pyridin-4-yl)-5-trifluoromethyl-furo[2,3-b]pyridine (hereinafter, referred to as “Present Active Compound 13”).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[OH:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[OH:40][C:41]1[CH:46]=[C:45]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(O)c2)c1
Temperature: 100 °C
Reaction time: 26 h
Yield: 57.4 %

Procedure:
To 400.0 mg (0.66 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 16 ml toluene were added 15.17 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 108.6 mg (0.79 mmol) (3-hydroxyphenyl)boronic acid in 4.0 ml ethanol and 118.3 mg (2.04 mmol) potassium fluoride in 4.0 ml water. The mixture was stirred at 100° C. for 26 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 236 mg (58%) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O.O>[OH:13][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 3-aminobenzenesulfonamide (2.35 g, 13.6 mmol) in 30% sulfuric acid (18 mL) stirred in a 0° C. ice-water bath was added dropwise a solution of sodium nitrite (1.22 g, 17.7 mmol) in water (10 mL). The resulting reaction solution continued to stir in an ice-water bath for 30 min. The solution was then stirred in a 100° C. oil bath for 30 min. After cooling to room temperature, the reaction solution was partitioned between ethyl acetate and brine. After shaking, the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered, and concentrated to a yellow solid (2.11 g, 89% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[N:11]=[C:12]([NH:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)C)[C:13]3[S:18][CH:17]=[C:16]([CH:19]=[CH2:20])[C:14]=3[N:15]=2)[CH2:3][CH2:2]1.[H][H]>CO.[Ni]>[CH2:22]([NH:21][C:12]1[C:13]2[S:18][CH:17]=[C:16]([CH2:19][CH3:20])[C:14]=2[N:15]=[C:10]([NH:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: C=Cc1csc2c(N[C@H](C)c3ccccc3)nc(NCCN3CCOCC3)nc12
Agent: [Ni]
Solvent: CO
Product: CCc1csc2c(NCc3ccccc3)nc(NCCN3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
Raney Ni was added to (R)—N2-(2-Morpholinoethyl)-N4-(1-phenylethyl)-7-vinylthieno[3,2-d]pyrimidin-2,4-diamine (10 mg, 0.025 mmol) in methanol (1 mL), and the mixture was stirred at room temperature for 24 hours under a pressure of a balloon filled with hydrogen gas. Filtration of the reaction mixture with celite followed by washing with methanol and concentration yielded the target compound (9 mg, 89% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:14])[CH3:13])[S:9][CH:10]=1.[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1OC>>[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:13])[CH3:14])[S:9][CH:10]=1
Reactant: COc1c(N)c(=O)c1=O
Reactant: CN(C)Cc1cc(OCCCN)cs1
Product: CN(C)Cc1cc(OCCCNc2c(N)c(=O)c2=O)cs1

Procedure:
An equimolar mixture of 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine [prepared according to the procedure described in published European Patent Application No. 27,744] and 1-amino-2-methoxycyclobutene-3,4-dione is reacted according to the general procedure of Example 19 to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[C:8]#[N:9].[S-2:12].[Na+].[Na+]>C(O)(C)(C)C.CC(O)C>[CH3:10][C:6]1[C:5]([CH3:11])=[N:4][NH:3][C:2](=[S:12])[C:7]=1[C:8]#[N:9]
Reactant: [S-2]
Reactant: Cc1nnc(Cl)c(C#N)c1C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: Cc1n[nH]c(=S)c(C#N)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-5,6-dimethylpyridazine-4-carbonitrile (100 mg, 0.60 mmol) and sodium sulfide was stirred in tert-butanol (2.0 mL) in a microwave reaction vial. The vial was sealed and irradiated at 100° C. for 10 minutes. LC/MS indicated product and no remaining starting material. The reaction solution was diluted with IPA (˜10 mL) and stirred at ambient temperature for about 15 minutes, then filtered. The solids on the filter were washed with IPA. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.24 min., m/z=166 [M+H]+.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH:21]([CH:2]=[O:4])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=CC(CCc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of potassium t-butoxide (0.673 g) in THF (20 mL) under nitrogen and cooled in an ice bath was added a solution of 1-(1-benzylpiperidin-4-yl)-4-phenylbutan-1-one from Step D (0.71 g) and methyl fornate (3.76 mL) in THF (12 mL) over 5 minute. The reaction was stirred for 15 min before being allowed to warm to rt for 2 h. The reaction was poured into water and extracted with ether (4×100 mL), methylene chloride (100 mL), and THF (100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrate under reduced pressure. The crude product was purified by FC on silica gel eluting with 5 and 20% methanol in ethyl acetate with 4% TEA to afford the title compound (0.8 g). 1H NMR (500 MHz, CDCl3) showed a 3:1 ratio of enol (δ 8.54 ppm) and aldehyde (δ 9.54 ppm) forms. Other signals from the two forms were only partially resolved. The title compound had a retention time of 9.47 min on a Zorbax SB-C18 column (4.6×75 mm) eluting with 20-100% gradient of acetonitrile in water with 0.1% TFA over 10 min at 1 mL per min.
Reaction SMILES: C1(C)C=CC(S([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH:21]4[O:23][CH2:22]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=O)=O)=CC=1.[NH2:25][CH:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][C:30]([OH:36])=[CH:31][CH:32]=2)[CH2:27]1>C(O)(C)C>[C:21]([OH:23])(=[O:36])[CH3:22].[OH:36][C:30]1[CH:29]=[C:28]2[C:33]([CH2:34][CH2:35][CH:26]([NH:25][CH2:22][CH:21]([OH:23])[CH2:20][O:19][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[CH:12]=[CH:11][NH:10]4)[CH2:27]2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Reactant: NC1CCc2ccc(O)cc2C1
Solvent: CC(C)O
Product: CC(=O)O
Product: Oc1ccc2c(c1)CC(NCC(O)COc1cccc3[nH]ccc13)CC2
Yield: 21.6 %

Procedure:
A mixture of 1-[1-(p-toluenesulfonyl)indol-4-yloxy]-2,3-epoxypropane (20 g), prepared as described in EP-A-228356, and 2-amino-7-hydroxytetralin (10.5 g) in isopropanol (300 ml) is heated to the reflux temperature for 4 hours. The solvent is then evaporated off under reduced pressure, the residue is dissolved in ethyl acetate and the organic solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up first in ethanol (200 ml) and then in a solution of sodium hydroxide (15 g) in water (90 ml). The reaction mixture is heated to the reflux temperature for 4 hours, made slightly acidic by the addition of 1N HCl and then basified by the addition of concentrated ammonium hydroxide. The reaction mixture is concentrated under reduced pressure, the residue is taken up in absolute ethanol and concentrated to dryness and this last procedure is repeated. The obtained residue is taken up in ethanol, filtered and washed on filter with ethanol. The filtrate and the washing ethanol are combined and the solution is basified by the addition of concentrated ammonium hydroxide. The residue which is obtained by evaporating off the solvent is purified by silica gel column chromatography eluting first with ethyl acetate and then with a mixture ethyl acetate/reethanol 9/1 v/v. The product-containing fractions are combined and evaporated to dryness. A mixture of acetic acid and isopropanol is used to take up the product. The precipitate which forms is then recovered by filtration and crystallized from 95% ethanol (60 ml) affording 2.6 g of N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-indol-4-yloxypropanamine acetate; m.p. 167°-170° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])(CC)C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(OCC)(=O)C>O1CCCC1>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Reactant: BrCCCCBr
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml, 1.3 M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1F.CC(C)([O-])C.[Na+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[Br:17])[C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(F)c1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(Br)c(N2CCN(Cc3ccccc3)C[C@@H]2CCO)c1

Procedure:
To a solution of (S)-2-(4-benzylpiperazin-2-yl)ethanol (150 mg, 0.681 mmol) and 1-bromo-2-fluoro-4-methylbenzene (167 mg, 885 mmol) in dimethyl sulfoxide (5 mL) was added sodium tert-butoxide (164 mg, 1.70 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature before addition of water and ethyl acetate. The organic layer was separated and concentrated onto silica gel. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J=7.80 Hz, 1H), 7.18-7.35 (m, 5H) 6.92 (d, J=1.36 Hz, 1H), 6.65-6.73 (m, 1H), 4.08 (t, J=6.44 Hz, 2H), 3.36-3.51 (m, 2H), 2.55-2.89 (m, 6H),1.87-1.99 (m, 1H), 1.68-1.77 (m, 2H); MS (APCI+) m/z 389, 391 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=S)[NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)[CH3:2].IC.O.[NH2:22][NH2:23].O>CO>[NH2:22][N:23]1[C:8](=[O:10])[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]1[N:3]([CH2:1][CH3:2])[CH2:17][CH3:18]
Reactant: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Reactant: NN
Solvent: CI
Solvent: CO
Solvent: O
Product: CCN(CC)c1nc2ccccc2c(=O)n1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Methyl 2-(3,3-diethyl-thioureido)benzoate (2.29 g, 8.59 mmol) was dissolved in methanol (15 mL), followed by addition of iodomethane (1.07 mL, 17.2 mmol). The reaction mixture was heated at 80° C. for 10 minutes under microwave conditions making sure the temperature did not exceed 80° C. The reaction mixture was evaporated to dryness and then redissolved in methanol (50 mL). Hydrazine monohydrate (1.25 mL, 25.8 mmol) was added followed by stirring at RT overnight. The reaction mixture was poured into water (200 mL), followed by extraction with diethyl ether (2×100 mL), drying (MgSO4) and evaporation in vacuo. The crude product was subjected to column chromatography (EtOAc/Heptane) giving the title compound (1.37 g, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15].[OH2:20]>>[CH2:18]([O:17][C:14](=[O:16])[CH:15]([C:6]([O:5][CH2:1][CH3:2])=[O:20])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:19]
Reactant: O
Reactant: CC(C)(C)OC(=O)NCCCCCl
Reactant: CCOC(C)=O
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-[(tert-butoxy)carbonyl]-4-chloro-butylamine (2.5 g, 0.012 mol) is then gradually added to the resulting mixture at room temperature. The reaction mixture is stirred at room temperature for 2 hours and at the reflux temperature for 6 hours, and then poured into ethyl acetate/water (1/1, v/v) (100 ml). The organic phase is separated, washed several times with water, and dried over MgSO4.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:6][CH3:7].[Cl-].[Cl-].[Cl-].[Al+3].Cl[CH2:28]Cl>>[CH2:5]([O:8][C:9]1[C:10]([C:1](=[O:3])[CH2:2][CH3:28])=[CH:11][C:12]2[C:13]([CH3:21])([CH3:22])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:6][CH3:7]
Reactant: CCCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCOc1cc2c(cc1C(=O)CC)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.831 g, 11.7 mmol) was added to a stirring solution of 3-n-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (Intermediate 6, 2.4 g, 9.7 mmol) in dichloromethane (100 mL), and the solution was cooled to 0° C. Aluminum trichloride (1.56 g, 11.7 mmol) was added over two to three minutes, the ice-bath was removed, the yellow solution was stirred for 1 h at room temperature. The solution was poured over ice in a separatory funnel, and the products were extracted three times with ether. The combined organic layers were washed with 10% aqueous sodium hydroxide, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound as a solid.