Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[N+]=[N-])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(N=[N+]=[N-])c2)COC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(N)c2)COC1

Procedure:
A solution of 740 mg (2.118 mmol) [5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (Example 31h) in 5 ml THF and 5 ml EtOH was stirred in the presence of 35 mg 10% Pd—C under hydrogen. After 3 h the mixture was filtered over celite, concentrated and crystallized from EtOAc/hexane to give a beige solid. The racemic product was separated via prep HPLC on Chiralpak AD-H 250×4.6 mm column using heptan/EtOH 1:1 as an eluent. The desired compound was the slower eluting (R)-enantiomer. TLC: Rf (Hexane/EtOAc 2:1)=0.15. HPLC: RtH=1.764 min; ESIMS [M+H]+=324. 1H-NMR (CDCl3, 360 MHz, broad signals due to hindered rotation): 10.5 (br, 1H), 7.12 (br, 1H), 6.69 (d, 1H), 6.59 (br d, 1H), 4.8-4.0 (m, 8H), 1.48 (br s, 9H).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:17][C:18](N)=[O:19].Cl>O>[O:19]=[C:18]1[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6][CH2:17]1
Reactant: NC(=O)CI
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CSCC(C(=O)O)N1
Reaction time: 1 h

Procedure:
A solution of 1.75 g (10 mmole) of L-cysteine hydrochloride monohydrate dissolved in 50 ml of water was adjusted to pH 8.0 with 1M sodium carbonate. Under nitrogen gas stream, 1.85 g (10 mmole) of monoiodoacetamide and 1M sodium carbonate were added alternately while maintaining pH at 8.0. After the reaction was carried out at room temperature for 1 hour, further the reaction was carried out in a sealed tube at 100° C. for 2 hours. To the reaction mixture was added 4N HCl to adjust the pH to 3.25, followed by concentration to dryness. The residue was extracted with hot ethanol, and after cooling, the crystals were collected by filtration and recrystallized from hot ethanol. Yield: 560 mg (34.8%), melting point: 182° to 184° C., Fab mass analysis [M+H]+= 162.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1([CH2:19][OH:20])[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=O.C(Cl)(Cl)(Cl)Cl.CN.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[C:3]=1[C:4]1[O:20][CH2:19][C:7]2([C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[N:6]=1
Reactant: COc1ccc2c(c1)CCCC2(CO)NC(=O)c1c(F)cccc1F
Agent: CN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(c1)CCCC21COC(c2c(F)cccc2F)=N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 600 mg (0.0017 mol) of the product of Step D in 9 mL of acetonitrile was added 1.8 mL CCl4 and 264 mg (0.0026 mol) of methylamine. Then, 678 mg (0.0026 mol) of triphenylphosphine was added. The mixture was stirred at ambient temperature for 15 minutes.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[O:16]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:12][O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: CC(=O)Oc1ccc(C2=COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(C2=COc3ccccc3O2)cc1
Yield: 77.4 %

Procedure:
A mixture of 4-(benzo[b][1,4]dioxin-2-yl)phenyl acetate (270 mg, 1.0 mmol) in MeOH:THF (5 mL: 3 mL) and K2CO3 (167 mg, 1.2 mmol) was stirred for 30 min at rt. The solvent was removed under reduced pressure and water was added. The solution was neutralized by dilute HCl and the solid was isolated by filtration, washed well with water and dried to give 175 mg of 4-(benzo[b][1,4]dioxin-2-yl)phenol (77%). MS (ES) m/z: 225.97 (M), 224.93 (M−1); Mp. 137-140° C.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)C1OC[C@H](C(C)(C)C)N=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:29][CH2:30][C@H:31]2[O:35][C@@H:34]([N:36]3[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]3=[O:38])[C@H:33]([OH:44])[C@@H:32]2[OH:45])=[CH:24][CH:23]=1.[C:60]1([N:66]=[C:67]=[O:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:29][CH2:30][C@H:31]2[O:35][C@@H:34]([N:36]3[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]3=[O:38])[C@H:33]([OH:44])[C@@H:32]2[O:45][C:67](=[O:68])[NH:66][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: CC(C)(C)[C@H]1COC(CC2=N[C@@H](C(C)(C)C)CO2)=N1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The THF solution (1 ml) containing 2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline] (0.02 mmol, 5.4 mg) and Cu(OTf)2 (II) (0.02 mmol, 7.2 mg) was stirred for 2 hours at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (1 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.2 mmol, 109 mg) and the THF solution (1 ml) of phenyl isocyanate (0.2 mmol, 23.8 mg) were added thereto. After the mixture was continuously stirred for 1 hour at 0° C. and overnight at room temperature, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 65:35, and the transformation ratio of the reaction was 89%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:24]=[C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH:15]=[CH:16][N:11]1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]2)=[CH:4][CH:5]=1
Reactant: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CCl)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccsc4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 mg (0.45 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one (example 4.1a) in 2.0 mL DCM is added 37 μL triethylamine (0.26 mmol) and subsequently 14 μL (0.18 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and additional 18 μL triethylamine (0.13 mmol) and 7 μL (0.09 mmol) methanesulfonyl chloride is added at RT and the reaction mixture is stirred 1 h at RT. 2.0 mL acetonitrile and 25 mg (0.18 mmol) N-piperidin-4-yl-acetamide are added and the reaction mixture is stirred for 1 h. A precipitate is formed and 1 mL of DMF is added and the reaction mixture is stirred overnight. The sole product formed (HPLC-MS analysis) is 1-[2-(4-chloromethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one. The reaction mixture is diluted with EtOAc, washed twice with water and is dried over MgSO4. After filtration, the solvent is evaporated and 30 mg (95% yield) of 1-[2-(4-chloromethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one is isolated. To 30 mg (0.09 mmol) 1-[2-(4-chloromethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one in 2.0 mL DMF is added 26 mg (0.18 mmol) N-piperidin-4-yl-acetamide and 37 mg (0.27 mmol) potassium carbonate at RT. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:14]([O-])(=[O:16])[CH3:15].[Na+]>C(OC(=O)C)(=O)C>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(OC)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.5 %

Procedure:
Methyl 3-hydroxy-4-(methyloxy)benzoate (27 g, 149 mmol.) was taken into acetic anhydride (150 mL) followed by addition of sodium acetate (24 g, 298 mmol.) and the resulting mixture was stirred at room temperature over 20 hours. The solid was filtered and washed once with ethyl acetate and the combined organic layers concentrated in vacuo to a slurry. The solid was collected by filtration, washed once with water and dried in vacuo to provide methyl 3-(acetyloxy)-4-(methyloxy)benzoate (25.9 g, 77% yield) as a white solid. 1H NMR (400 MHz, CDCl3): 7.92 (dd, 1H), 7.70 (d, 1H), 6.97 (d, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][N:2]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([O:10][CH3:9])=[O:20])=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CNc1ccccn1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methylaminopyridine (1.0 mmol) and methyl-4-formylbenzoate (1.0 mmol) were mixed in THF (2 mL) and dibutyltin dichloride (0.1 mmol) was added. After stirring at RT for 10 minutes, phenylsilane (1.1 mmol) was added and the reaction mixture allowed to stir at room temperature for a further 17 h. The reaction mixture was then concentrated by N2 stream and the residue purified by flash chromatography (silica gel, heptane:EtOAc) to give methyl 4-[methyl(pyridin-2-yl)amino]methylbenzoate: m/z=257 in MS ES+ as a yellow oil which was used directly in the subsequent step.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:38][C@H:39]1[C@@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:42](OC(=O)C)[O:41][C@@H:40]1[C:52]1[N:56]=[C:55]([CH2:57][CH3:58])[O:54][N:53]=1)(=[O:37])[CH3:36]>>[C:45]([O:44][C@@H:43]1[C@H:39]([O:38][C:35](=[O:37])[CH3:36])[C@@H:40]([C:52]2[N:56]=[C:55]([CH2:57][CH3:58])[O:54][N:53]=2)[O:41][C@H:42]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=2[NH:10][CH2:9][CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:47])[CH3:46]
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCc1nc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Agent: Cl
Product: CCc1nc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-(5-ethyl-1,2,4-oxadiazol-3-yl)tetrahydro-3-furanyl acetate (Preparation 38).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C)[CH2:25][CH2:24]2)(=[O:22])=[O:21])[C:14]=1[OH:33])=[O:11].FC(F)(F)C(O)=O.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([S:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:28]2)(=[O:22])=[O:21])[C:14]=1[OH:33])=[O:11]
Reactant: COCCN1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(F)c3Cl)c2O)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCN(CCO)CC2)c1O)Nc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Under Ar, to the suspension of 2c trifluoroacetic acid salt (100 mg, 0.16 mmol) in 3 mL of dichloromethane was added boron tribromide (0.63 mL, 0.63 mmol). The mixture was stirred at room temperature overnight. After quenching with methanol, solid produced. The mixture was filtered, solid was collected. Purification upon Gilson HPLC, eluting with acetonitrile/water/0.1% TFA (10/90, v/v to 90/10, v/v, over 10 min) yielding 66 mg (76%) of the title compound 2d. LC-MS (m/z) 507.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].CSC(NCC1C=NC=CC=1)=C[N+]([O-])=O.CN>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:18][NH2:19])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: NN
Agent: CN
Agent: CSC(=C[N+](=O)[O-])NCc1cccnc1
Solvent: O
Product: NNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1

Procedure:
The reaction procedure of Example 3 was repeated except that 1-(6-chloro-3-pyridylmethyl)amino-1-methylthio-2-nitroethylene and hydrazine hydrate were used in lieu of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene and aqueous methylamine solution, respectively. The procedure gave the title compound as pale yellow crystals.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([NH:19]C(=O)C)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CCO>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 86.8 %

Procedure:
To a solution of N-[2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-yl]-acetamide (679 mg, 2.15 mmol) in EtOH (36 mL) was added concentrated hydrochloric acid (7.2 mL). The mixture was heated at reflux for 2 h. After cooling, the mixture was neutralized with 15% sodium hydroxide. The volatiles were removed under reduced pressure and the residue was dissolved in methanol (10 mL). The mixture was filtered and the filtrate was concentrated in vacuo to give 512 mg (87%) of 2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylamine.
Reaction SMILES: [CH:1]1C=CC2NC=C(CCO)C=2C=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]1[C:40]([CH3:41])([CH3:1])[O:39][CH2:37][CH2:36][C:30]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93°-95° C., is prepared by lithium aluminum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Pat. No. 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67-7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyl chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[CH2:14][CH:13]=2)=[C:8]([F:26])[C:7]=1[F:27])[CH2:2][CH2:3][CH3:4].C([Li])(CC)C.B(OC)(OC)[O:34]C.Cl>CCCCCC.C1CCCCC1.C(OCC)(=O)C.C1COCC1>[CH2:1]([O:5][C:6]1([OH:34])[CH:11]=[CH:10][C:9]([C:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[CH2:14][CH:13]=2)=[C:8]([F:26])[CH:7]1[F:27])[CH2:2][CH2:3][CH3:4]
Reactant: COB(OC)OC
Reactant: CCCCOc1ccc(C2=CCC(c3cccc(F)c3F)CC2)c(F)c1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCCCOC1(O)C=CC(C2=CCC(c3cccc(F)c3F)CC2)=C(F)C1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
1-Butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (s-20) (7.2 g) and THF (200 ml) were put in a reaction vessel under an atmosphere of nitrogen and cooled to −74° C. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 23.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, trimethyl borate (2.0 g) in a THF (30 ml) solution was added dropwise thereto in the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. Then, the reaction mixture was poured into a vessel containing 1 N hydrochloric acid (100 ml) and ice-water (200 ml), and mixed with them. Ethyl acetate (200 ml) was added and the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and salt water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue and acetic acid (50 ml) were put in a reaction vessel under an atmosphere of nitrogen, and hydrogen peroxide (a 31% aqueous solution; 1.0 g) was added in the temperature range of 25° C. to 30° C., and then the stirring was continued for another 2 hours. Then, the reaction mixture was poured into a vessel containing an aqueous solution of sodium hydrogensulfite (100 ml) and ethyl acetate (200 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water and salt water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to give 1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorophenol (s-21) (5.9 g). The yield based on the compound (s-20) was 78.6%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10]>[Pd].C(OCC)(=O)C>[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cccc(OC(F)(F)F)c1
Reaction time: 18 h

Procedure:
0.69 g of 5% palladium on activated carbon was added, under a nitrogen atmosphere, to 15 g of 3-(trifluoromethoxy)-cinnamic acid in about 125 ml of ethyl acetate p.a., and hydrogenation was then carried out for 18 hours at room temperature under a hydrogen pressure of 2 bar. Filtration over kieselguhr was then carried out, followed by washing three times with ethyl acetate, and the combined filtrates were concentrated in vacuo at from 25 to 40° C. (yield 15.8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:11][CH3:12])[C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:24][CH:25]1[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1>C1(C)C=CC=CC=1>[C:25]1([CH2:24][N:1]2[CH2:6][CH2:5][CH:4]([N:7]([CH2:11][CH3:12])[C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=1
Reactant: CC1Cc2ccccc21
Reactant: CCN(C(C)=O)C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCN(C(C)=O)C1CCN(CC2=Cc3ccccc32)CC1

Procedure:
3.3 g of N-piperid-4-yl-N-ethylacetamide and 2.8 g of 1-methylbenzocyclobutene tosylate (prepared in accordance with the process described in J.A.C.S., (1975), 154, p. 347) are refluxed under nitrogen for 20 hours in 16 ml of toluene. After cooling, the reaction mixture is evaporated to dryness and taken up in diethyl ether. After extraction with N hydrochloric acid, the extract is rendered basic in the presence of diethyl ether and the organic phase is washed with water, dried over magnesium sulphate and evaporated in vacuo to yield N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylacetamide. The corresponding hydrochloride is obtained in ethyl acetate in the presence of ethereal hydrogen chloride.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.[NH2:8][C:9]([NH2:11])=[S:10]>>[CH:5]1([C:3]2[N:8]=[C:9]([NH2:11])[S:10][CH:2]=2)[CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CC1
Reactant: NC(N)=S
Product: Nc1nc(C2CC2)cs1

Procedure:
A mixture of 2-bromo-1-cyclopropyl-ethanone (0.50 g, 3.0 mmol, Waterstone Technology) and thiourea (0.23 g, 3.1 mmol) were processed as in Example 71A to afford the title compound. MS (DCI/NH3) m/z 141 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])[CH:21]=[CH:22][CH:23]=4)=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.P(Br)(Br)Br>ClCCCl>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[O:26])[CH:21]=[CH:22][CH:23]=4)=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH:5]=[CH:4]1
Reactant: COc1ccc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: BrP(Br)Br
Solvent: ClCCCl
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(=O)[nH]c4)ccn23)c1
Temperature: 80 °C
Yield: 124.2 %

Procedure:
To 1-{3-[7-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (0.187 g, 0.226 mmol) in DCE (10 ml) was added PBr3 (0.174 ml). The reaction was heated at 80° C. for 3 hours, then partitioned between EtOAc and water, insoluble material filtered off and dried to give 1-{3-[7-(6-Oxo-1,6-dihydro-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (0.12 g) MS: [M+H]+428