Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9](=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:20])=[N-]>CCOCC>[C:1]1([C:7]2[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:20])=[O:15])[C:9](=[O:17])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC1CCC(c2ccccc2)=CC1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CC1CCC(c2ccccc2)=CC1=O

Procedure:
A solution of 4-phenyl-2-oxo-3-cyclohexene-1-acetic acid (Tet. Lett. 1968, 4739) (10.0 g, 43.4 mmol) in Et2O (150 ml) was treated with ethereal diazomethane at 0° C. until TLC indicated the reaction to be complete. The solvent was evaporated to yield methyl 4-phenyl-2-oxo-3-cyclohexene-1-acetate (10.6 g, quant.): Rf 0.33 (20% EtOAc in hexane);
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:12][C@H:10]1[CH2:11][C@H:8]([NH2:7])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of (trans-3-benzyloxycyclobutyl)carbamic acid tert-butyl ester (0.99 g, 3.56 mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture stirred at RT for 3 h. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and loaded onto an SCX-2 (20 g) cartridge. The cartridge was washed with DCM then MeOH and then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow oil (0.6 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.36-7.31 (5H, m), 4.40 (2H, s), 4.29-4.20 (1H, m), 3.75-3.65 (1H, m), 2.39-2.26 (2H, m), 2.02-1.90 (2H, m), 1.49 (2H, s, br).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](=[N:16]O)[CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:6][CH2:5][C:4]1=[O:25])[CH3:2].[H][H]>C(O)C.[Ni]>[NH2:16][CH:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:3]([CH2:1][CH3:2])[C:4](=[O:25])[CH2:5][N:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:8]=2[CH:13]=1)[CH3:15]
Reactant: [H][H]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=NO)ccc21
Agent: [Ni]
Solvent: CCO
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)N)ccc21

Procedure:
A solution of 1 g (2.95 mmol) of 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-2H-1,4-benzodiazepin-2-one in 150 ml of ethanol is stirred with 1.0 g of Raney-nickel paste for 21 hours in a hydrogen atmosphere at 50°. After filtration over Digalite and evaporation in vacuo, there is obtained 7-(1-aminoethyl)-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 53°-55°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[N:5][N:6]=1.[C:14]([C:21](OCC)=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:8]([N:7]([CH2:11][CH2:12][CH3:13])[C:4]1[S:3][C:2]2=[N:1][C:21](=[O:22])[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:6]2[N:5]=1)[CH2:9][CH3:10]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CCCN(CCC)c1nnc(N)s1
Solvent: CCO
Product: CCCN(CCC)c1nn2c(C(=O)OCC)cc(=O)nc2s1

Procedure:
The procedure used was as in Example 5. However, there were reacted 10 g of 2-amino-5-[di-(n-propyl)amino]-1,3,4-thiadiazole and 8.5 g of diethyl acetylenedicarboxylate in the presence of 200 ml of ethanol to give 10.2 g (63% of the theoretical yield) of ethyl 2-[di-(n-propyl)amino]-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylate, melting at 95°-97° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 70 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using thiomorpholine instead of isopropylamine, to the title compound (47 mg, 70%) which was obtained as a colourless gum. MS: m/e=398.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>>[CH3:19][C:18]1[N:1]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=2)[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: NCCCc1ccc(C(N)=O)s1
Reactant: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1CCCc1ccc(C(N)=O)s1

Procedure:
5-(3-Aminopropyl)-2-thiophenecarboxamide is reacted with acetonylacetone to give 5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide, m.p. 144°-126° C. (see J. Chem. Soc. Chem. Commun. 800 [1982]). This is alkylated with n-butyl bromide to give N-butyl-5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide (see Synthesis 266 [1976]). The latter is cleaved with hydroxylamine hydrochloride to give 5-(3-aminopropyl)-N-butyl-2-thiophenecarboxamide.
Reaction SMILES: O[C:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].[H][H]>FC(F)(F)C(O)=O>[C:3]1([CH:2]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCc2cc(C(O)(c3ccccc3)c3cccnc3)ccc2N1
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2cc(C(c3ccccc3)c3cccnc3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 240 mg of 6-[1-hydroxy-1-phenyl(3-pyridyl)methyl]-3,4-dihydrocarbostyril in 5 ml of trifluoroacetic acid at 0° C. was added 280 mg of sodium borohydride. When hydrogen evolution ceased the mixture was stirred at 25° C. for 30 minutes, then the solvent was removed under reduced pressure. The residue was added to aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride to give 6-[phenyl(3-pyridyl)methyl]-3,4-dihydrocarbostyril, m.p. 95°-96° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Reaction time: 8 h

Procedure:
A solution of 3-(1-t-butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-one (4.80 g, 13.9 mmol) in ethyl acetate (300 mL) was saturated with hydrogen chloride gas at 0° C. The reaction was allowed to warn to room temperature and stirred overnight. The solid was filtered and washed with ethyl acetate. The ethyl acetate filtrate was concentrated for a second crop. The title compound was obtained as a solid (2.94 g). MS 246 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.10 (m, 2H), 6.94 (d, J=8 Hz, 1H), 6.91 (t, J=8 Hz, 1H), 4.35 (tt, J=10, 1 Hz, 1H), 3.52 (m, 4H), 3.12 (t, J=12 Hz, 2H), 3.05 (m, 2H), 2.07 (qd, J=12, 4 Hz, 2H), 1.99 (m, 2H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].S(=O)(=O)(O)O.[CH3:12][C:13](=[CH2:15])[CH3:14]>O>[F:3][C:2]([F:5])([F:4])[CH2:1][O:6][C:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: C=C(C)C
Reactant: OCC(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OCC(F)(F)F
Temperature: 20 °C
Yield: 51 %

Procedure:
Approximately 55 g (0.55 mol) trifluoroethanol and 2 g concentrated sulfuric acid were placed in a 300 ml glass pressure bottle equipped with a magnetic stir bar and pressure gauge. The pressure bottle was evacuated briefly and the stirred contents were cooled in a water bath at about 20° C. in order to moderate the temperature of the somewhat exothermic reaction with isobutylene. Isobutylene was then added to a pressure of about 20 psig. The isobutylene supply was turned off and the reaction was monitored by the decrease in pressure in the glass reactor. After the pressure had fallen to 0 psig, additional isobutylene was charged. In this manner, a total of 20.1 g (0.359 mol) isobutylene was added. The mixture was then poured into 300 ml of cold water and extracted with 50 ml of dodecane. The organic layer was separated, washed with three (3) 50 ml portions of water and dried over anhydrous powdered magnesium sulfate. The organic layer was distilled affording 28.5 g (51%) tertiary butyl 2,2,2-trifluoroethyl ether, bp 82.5°-84° C. 1H NMR (CDCl3): δ 3.77 (q, 2H, J=8 Hz), 1.25 (s, 9 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]([CH3:21])([CH3:20])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:19][C@H:16]1[CH2:17][CH2:18][C@@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: CC1(C)C[C@H](N)CC[C@@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2.15 g, 11.6 mmol)), (1S,4R)-4-amino-2,2-dimethylcyclohexanol (1.51 g, 10.5 mmol) and DIEA (2.72 g, 21.1 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. After removal of the organic solvent under reduced pressure, the residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (15% ethyl acetate in petroleum) to afford the title compound as a pale yellow solid (2.2 g, 7.53 mmol, 72% yield). MS (ESI) m/z 293.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[C:10](OC)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([CH2:1][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(C)n1
Reactant: COC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
A mixture of 4-methyl-2-methylthio-pyrimidine (30 g, 0.21 mol) and methyl benzoate (30 g, 0.21 mol) is added to a solution of potassium tert-butoxide (54 g, 0.48 mol) in tetrahydrofuran (350 ml) with cooling in such a way that the reaction temperature does not exceed +20° C. After stirring the mixture for additional 20 minutes the solution is poured onto crushed ice. The resulting solution is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Drying of the organic phase, filtering and evaporation of the solvent under reduced pressure gives the 2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone in form of a mixture of tautomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Yield: 70.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.06 g, 2.5 mmol) was reacted with NBS (0.5 g, 2.8 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.89 g, 71%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:33][C:28]1[N:29]=[C:30]([CH3:32])[N:31]=[C:26]([C:25]2[C:20]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[N:27]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(NS(=O)(=O)N3CCOCC3)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a 15 mL RB flask was added N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.065 g, 0.222 mmol), 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.055 g, 0.266 mmol), and DMF (3.0 mL). The mixture was cooled to 0° C. under N2. sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.888 mL, 0.888 mmol) was added to the solution in one portion. The now dark brown mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (42.0 mg). MS (ESI pos. ion) m/z: 478.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.15 (br. s., 4H) 3.61 (br. s., 4H) 7.03 (dd, J=7.53, 4.60 Hz, 1H) 7.79 (br. s., 1H) 7.91 (br. s., 1H) 8.38 (d, J=3.36 Hz, 1H) 8.51 (s, 1H) 8.82 (d, J=5.41 Hz, 2H) 9.78 (s, 1H) 12.26 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][CH:10]=1)C=C.[BH4-].[Na+]>O1CCCC1.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>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[CH:11]([O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)[C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=1
Reactant: C=CCOc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(O)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 22) (2.35 g) in tetrahydrofurane (40 mL) is added tetrakistriphenylphosphinepalladium (0.344 g). The mixture is stirred for 5 min at room temperature, then sodium borohydride (0.576 g) is added. The mixture is stirred for 20 h at room temperature, filtered over a clarcel pad. The pad is rinsed with ethyl acetate. Pooled organic phases are washed with aqueous ammonium chloride solution, then sodium hydrogenocarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by three column chromatographies over silica gel (twice gradient heptane/ethyl acetate from 95/5 to 80/20, third eluant heptane/dichloromethane 5/1). Pooled fractions are concentrated under reduced pressure. The residue is dissolved in methanol, refluxed for 5 h and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia from 100/0 to 90/10/1) to give 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol as a beige solid melting at 201° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1Br)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1ccsc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccsc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
2-Bromothiophene-3-carboxylic acid methyl ester (3.0 g, 14.0 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g, 14.0 mmol, 1.0 eq.), THF (150 mL) and Na2CO3 (28 mL, 56 mmol, 4.0 eq.) were combined. The mixture was degassed and purged with nitrogen (3×). PdCl2(PPh3)2 (0.3 g, 0.4 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3×), then heated at 80° C. overnight. The mixture was then cooled and the layers were separated. The THF layer was diluted with EtOAc (150 mL), washed with saturated aqueous NaCl (50 mL) and dried over Na2SO4. The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1˜10:1) to yield 4-(3-methoxycarbonylthiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nccc(-c2cccc(CNCc3ccccn3)c2)n1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)Cc1ccccn1

Procedure:
Intermediate 10 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution (0.1 M) of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate in DMF was treated at 0° C. with NaH (1.3 eq.) and then stirred at 25° C. for 1 h. The solution was treated with tert-butylbromoacetate (1.2 eq.) and stirred 25° C. for 12 h. The mixture was diluted with EtOAc and washed sequentially with HCl (1 N) and brine. The dried organic phase was concentrated and the residue purified by flash chromatography on silica gel (5:95 EtOAc/PE) to afford the title compound (83%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.31-1.53 (m, 3H), 1.42 (s, 9H), 1.64-2.02 (m, 7H), 2.77-2.96 (m, 1H), 3.88 (s, 3H), 5.12 (s, 2H), 7.68 (dd, J 8.4, 1.2, 1H), 7.84 (d, J 8.4, 1H), 8.16 (d, J 1.2, 1H); MS (ES+) m/z 452 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=O.[CH:14]([NH2:16])=O.[OH-].[Na+]>CCOC(C)=O>[CH3:1][N:2]1[CH:3]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[N:16]=[CH:14]1
Reactant: NC=O
Reactant: CNCC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2ccc(C#N)cc2)c1

Procedure:
4-(N-Methylglycyl)benzonitrile (2.6 g) and 20 ml of formamide were heated in a microwave tube at 210° C. for 20 min. The reaction was diluted with EtOAc, made basic with 15% aq NaOH, washed with water (3×100 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (70% EtOAc in hexanes to 100% EtOAc) to give 1.05 g of 4-(1-methyl-1H-imidazol-4-yl)benzonitrile. LCMS: M+1=184.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)[CH:3]=3)[N:34]=2)=[CH:26][CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: c1ccc(COc2ccc(-c3nc(COc4cccc(CCCn5ccnc5)c4)co3)cc2)cc1
Yield: 81 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(4-benzyloxyphenyl)-4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 81%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 144-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8](CCCl)[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1.[CH2:18]([CH2:25][NH2:26])[C:19]1C=C[CH:22]=[CH:21][CH:20]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C.C(O)(C)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([NH:26][CH2:25][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:27]=3[CH3:28])[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Reactant: NCCc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: Cc1ccccc1CNC1CN(C)C(=O)c2cc(Cl)cnc2O1
Yield: 47.9 %

Procedure:
To a solution of 6.0 g (0.022 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one in 50 ml of absolute ethanol was added 5.3 g (0.044 mole) of benzylmethylamine and the mixture heated to reflux for three days. The solvent was removed by rotary evaporation, and the residue was taken up in 100 ml of methylene chloride, which was subsequently washed with 2×50 ml of dilute sodium hydroxide and 50 ml water, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Residual benzylmethylamine was removed at 95° C., 0.5 mm Hg. However, the mass spectrum now showed starting material; therefore, the residue was taken up in 50 ml of absolute ethanol. To the resulting solution was added 2.7 g (0.022 mole) of benzylmethylamine and the mixture heated to reflux for 24 hrs. The reaction mixture was subjected to the same work-up as mentioned before. The syrup was treated with oxalic acid in isopropyl alcohol. The resulting crystals were recrystallized from ethanol/isopropyl alcohol to give 4.7 g (47.9%) of white crystals, m.p. 176°-179° C.