Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[CH:6][NH:7]2.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[CH:6][NH:7]2
Reactant: COc1ccc(-c2c[nH]c3c(OC)ccc(F)c3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccc(O)cc2)c[nH]c2c(O)ccc(F)c12
Temperature: -10 °C
Reaction time: 15 h
Yield: 39.7 %

Procedure:
5-Fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (1.0 g, 3.34 mmol) was suspended in dichloromethane (40 ml), and the suspension was cooled to −10° C. in a methanol-ice bath. A 1N boron tribromide (17 ml) was added thereto, and the resulting mixture was stirred at room temperature for 15 hours. Ice water and dichloromethane were added to the reaction mixture, and the resultant insoluble matter was collected by filtration. The substance remaining on the filter was washed with water, dried and purified by silica gel column chromatography (dichloromethane:methanol=20:1→8:1→4 ethyl acetate:methanol=4:1). The purified product was concentrated under reduced pressure and ethyl acetate was then added to crystallize the residue. The crystals were collected by filtration, washed with ethyl acetate, and dried to thereby obtain 360 mg of powdery pale gray 5-fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinolin-4-one (yield: 40%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]2[CH:9]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]([C:15]([F:14])([F:27])[C:23]([F:25])([F:24])[F:26])[O:13][C:7]=2[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C=CC(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
A mixture of 4-tert-butylsalicylaldehyde Example 8, step 1 (1.15 g, 6.4 mm) and the ethyl ester from Step 2 (1.59 g, 7.3 mmol) was dissolved in anhydrous DMF (4 mL). With stirring, K2CO3 (1.10 g, 9.0 mmol) was added causing the reaction to become deep red. The reaction was stirred at room temperature for 100 hours, acidified with 3 N HCl, diluted with ethyl acetate and washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate/hexanes to afford a yellow oil (1.72 g, 70%): 1H NMR (CDCl3/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 7.04 (dd, 1H, J=8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J=22.4 Hz 3.0 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.30 (s, 9H).
Reaction SMILES: [N:1]1([C:7]([O:9][C@H:10](/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[CH2:28])[O:19][C@@H:18]2[CH3:30])=[O:15])[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:31]([C@H:33]1[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][C@:35]2([O:37][CH2:36]2)[C@@H:34]1[OH:43])=[CH2:32].C1(=O)C=CC(=O)C=C1>C(Cl)CCl>[CH:31]([C@H:33]1[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][C@:35]2([O:37][CH2:36]2)[C@@H:34]1[OH:43])=[CH2:32].[N:1]1([C:7]([O:9][C@@H:10]([CH3:11])/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[CH:28]/[C@H:33]3[O:40][C:39]([CH3:41])([CH3:42])[CH2:38][C@:35]4([O:37][CH2:36]4)[C@@H:34]3[OH:43])[O:19][C@@H:18]2[CH3:30])=[O:15])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C=C/C(C)=C/C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Agent: C=C[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O
Agent: O=C1C=CC(=O)C=C1
Solvent: ClCCCl
Product: CC(/C=C/[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Temperature: 42 °C

Procedure:
A solution of (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (18 mg, 0.099 mmol) was prepared in ClCH2CH2Cl (200 μL) at 23° C. under an open atmosphere. To a stirred solution of (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate (26 mg, 0.062 mmol) in ClCH2CH2Cl (200 μL) was added the solution of (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (100 μL), benzoquinone (1.4 mg, (0.012 mmol), followed by Grela catalyst (1.5 mg, 2.2 μmol) at 23° C. under an open atmosphere. The reaction mixture was then heated to 42° C. After 3 h at the same temperature, additional Grela catalyst (1.5 mg, 2.2 μmol) and (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (100 μL) were added. After 11 total hours, the reaction was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10→80% EtOAc in hexanes) on silica gel (8 mL) to give (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-Pentenamide (10.4 mg, 29%), and a mixture of (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate and (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (22.1 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[CH:11]=1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[CH:20]=[O:21]
Reactant: Clc1ccc2nc(Cl)cn2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(Cl)nc2ccc(Cl)cn12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Compound 12 (1.0 g, 5.4 mmol) was dissolved in DMF (5 mL) and the solution cooled to 0° C.in an ice-water bath. To this solution was added POCl3 (0.6 mL, 6.4 mmol) and the mixture stirred for 15 min. The bath was removed and the mixture warmed to room temperature and stirred for 3 hours. This reaction mixture was poured into ice water. The aqueous suspension was made basic by the addition of concentrated NH4OH and the precipitated solid collected by filtration. This solid was dissolved in CHCl3 (50 mL) and the solution extracted with water (3×50 mL), dried (MgSO4) and solvent removed under reduced pressure to give 1.0 g (87%) of compound 50 as a white solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1([F:16])[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([NH2:15])[C:8]=2[O:7]1.Cl.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].C([O-])(=O)C.[Na+]>O.CO>[F:16][C:6]1([F:5])[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:15][N:1]=[C:20]([C:19](=[O:24])[CH3:18])[C:21](=[O:23])[CH3:22])[C:8]=2[O:7]1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Reactant: Nc1cccc2c1OC(F)(F)O2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)C(=NNc1cccc2c1OC(F)(F)O2)C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A solution of sodium nitrite (0.96 g, 14 mmol) in H2O (5 mL) was added dropwise to a solution of 2,2-difluoro-1,3-benzodioxol-4-amine (2.0 g, 12 mmol) in 6 M HCl aqueous solution (12 mL, 72 mmol) at 0° C. After stirring for 15 min at 0° C., the mixture was added to a suspension of 2,4-pentanedione (1.2 mL, 12 mmol) and sodium acetate (5.9 g, 72 mmol) in MeOH (20 mL) pre-cooled at 0° C. The formed precipitate was collected by filtration, washed with water and dissolved in AcOEt. The organic solution was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.0 g, 90% yield) as orange crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.49 (3H, s), 2.63 (3H, s), 6.88 (1H, dd, J=8.0, 1.1 Hz), 7.13 (1H, t, J=8.1 Hz), 7.30 (1H, dd, J=8.5, 1.1 Hz), 14.56 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.Cl.C[N:22](C)[CH2:23][CH2:24]CN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N)C>O1CCCC1.C(Cl)(Cl)Cl.O>[CH2:23]([NH:22][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:4]=1)[CH3:24]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CCN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 24 h
Yield: 94.8 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.3 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g) and 3H-[1,2,3] 1-hydroxy-7-azabenzotriazole (0.077 g) was added to a stirred solution of ethylamine in tetrahydrofuran (2M, 5 ml) in chloroform (30 ml) and the mixture was stirred for 24 h. The mixture was poured into water, passed through a hydrophobic filter tube and the organic phase was concentrated under vacuum. The residual solid was purified on an SCX cartridge eluting with methanol to give the title compound as a pale yellow solid (1.36 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH3:14])=[O:12]>N1C=CC=CC=1.C(Cl)Cl>[CH3:14][O:13][C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:12]
Reactant: COC(=O)Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of 10 g of indoline in 10 ml of pyridine is cooled to 0° C., a solution of 7.9 g of methyl chloroformate in 10 ml of DCM is added dropwise and the mixture is stirred for 1 hour at 0° C. A further solution of 7.9 g of methyl chloroformate in 10 ml of DCM is then added and the reaction mixture is concentrated under vacuum. The residue is taken up with water and extracted with AcOEt, the organic phase is washed with a 5% solution of potassium hydrogensulfate, with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 8.3 g of the expected product after trituration in a DCM/iso ether mixture and then filtration. M.p.=69°-70° C.
Reaction SMILES: FC(F)(F)C1C=CC(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=CC=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:26]=[CH:25][C:23]([NH:24][N:10]=[C:11]2[C:12]([NH2:13])=[N:36][N:35]=[C:14]2[NH2:15])=[CH:22][CH:21]=1
Reactant: N#CC(C#N)=NNc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(C(F)(F)F)cc1
Temperature: 75 °C

Procedure:
4-[(4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 119 mg (0.5 mmol) of 2-[(4-trifluoromethylphenyl)hydrazono]malononitrile, which was derived from 4-(trifluoromethyl)aniline (126 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. No precipitate had formed after heating at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 67 mg (50%) of the compound as a greenish brown solid; 1H NMR (ppm, DMSO-d6): 6.03 (br s, 2H), 6.48 (br s, 2H), 7.63 (d, 2H), 7.80 (d, 2H), 10.80 (br s, 1H).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].C(N(CC)CC)C.[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C1(C)C=CC=CC=1>[CH2:7]([N:9]1[C:18]([OH:23])=[CH:19][C:20]([CH3:22])=[N:10]1)[CH3:8]
Reactant: CCNN
Reactant: COC(=O)CC(C)=O
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1nc(C)cc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3.9 g of ethyl hydrazine oxalate and 3.6 ml of triethylamine in 80 ml of toluene was stirred at room temperature for 15 min. 2.8 ml of methyl acetoacetate was added and the mixture was azeotroped for 1.5 h. The mixture was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (97:3) for the elution to give 3.1 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:3]=1.Cl[C:12](OC1C=CC=CC=1)=[O:13].C(N(CC)CC)C.[Br:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][C:30]=1[CH2:35][CH3:36]>C(#N)C>[Br:28][C:29]1[S:33][C:32]([NH:34][C:12]([NH:10][S:7]([C:4]2[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=2)(=[O:9])=[O:8])=[O:13])=[N:31][C:30]=1[CH2:35][CH3:36]
Reactant: CCc1nc(N)sc1Br
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(S(N)(=O)=O)cs1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc(NC(=O)NS(=O)(=O)c2csc(C)c2)sc1Br
Temperature: 57.5 °C
Reaction time: 1.25 h

Procedure:
5-Methyl-thiophene-3-sulfonic acid amide (0.0496 g, 0.28 mmol) was dissolved in 1.5 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.0443 g, 1.01 eq.) and triethylamine (0.097 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1.25 h. The above prepared 5-bromo-4-ethyl-thiazol-2-ylamine (0.061 g, 1.05 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 55-60° C. over night. Cooling, pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, MeOH/ethyl acetate=1/99), yielded eventually, after precipitation from ethyl acetate/heptane, 0.038 g of the title compound as off-white solid.
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CC(C)OC(=O)Cl
Product: CCO[C@H]1CN(C(=O)OC(C)C)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting isopropyl chloroformate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34–7.26, 5.22, 4.95, 4.75, 4.08, 3.96, 3.73, 3.60, 3.50, 3.38, 3.25, 2.71, 2.47, 1.32–1.25, 1.16; HRMS (FAB) calcd for C24H32Cl2N4O3+H 495.1929, found 495.1909. Anal. Calcd for C24H32Cl2N4O3: C, 58.18; H, 6.51; N, 11.31. Found: C, 58.43; H, 6.64; N, 11.25.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]1([CH2:14][CH2:15][CH2:16]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([CH2:14][CH2:15][CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a stirred solution of imidazole (6.808 g, 0.1 mol) in dry DMF (100 ml) at 0° C. under argon was added portionwise 4 g (0.1 mol) of 60% sodium hydride and the mixture was stirred for 30 minutes at room temperature, and cooled to 0° C. To the above mixture was added 3-phenylpropyl bromide (19.91 g, 0.1 mol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was heated on a steam-bath for 4 hours and stirred at room temperature overnight. The solvent was concentrated in vacuo, the residue was partitioned between methylene chloride and water, the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residual oil was dried in vacuo and purified by silica gel column chromatography to afford 16.1 g (86%) of 1-(3-phenylpropyl)imidazole.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])O)[CH2:8][CH2:9][C:10]=2[N:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: COc1ccc(C(O)CCN2CCc3nc(N)sc3CC2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)c(OC)c1
Reaction time: 1 h

Procedure:
0.45 g (1.2 mmol) of 2-amino-6-(3-(2,4-dimethoxy-phenyl)-3-hydroxy-1-propyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine are stirred in 35 ml of anhydrous toluene together with 0.47 g (2.7 mmol) of p-toluenesulphonic acid hydrate and 7 g of molecular sieve (4Å) in a bath at 40° C. After one hour, a further 5 g of molecular sieve are added and after a total of 2 hours a further 2.5 g of molecular sieve are added. After a total of 3 hours at 40° C. the mixture is filtered through a glass frit coated with Celite and the filter cake is washed out several times with chloroform. The toluene and chloroform solutions are extracted with semi-concentrated ammonia and with water, then dried and filtered and evaporated down in vacuo. The combined evaporation residues are purified by column chromatography on silica gel (toluene/ethyl acetate/methanol/conc. ammonia=4:3:1:0.5). Yield: 43 mg (10% of theory), Melting point: 95°-100° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.I[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:17][CH2:18][CH3:19])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Temperature: 50 °C
Yield: 46.2 %

Procedure:
A mixture of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.6 mmol), 1-iodopropane (1.2 g, 6.9 mmol) and sodium carbonate (0.9 g, 8.5 mmol) in DMF (40 ml) was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue treated with water (60 ml) and extracted with ethyl acetate (3×80 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated. The residue was triturated with ether/cyclohexane, the solid was filtered off and dried to afford the title compound (0.82 g, 46%); m/z 269.1 [MH+].
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC.O>[ClH:2].[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N:10]1[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]1
Reactant: CN(CCCl)CCCl
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COC(=O)c1ccc(OC)c(N2CCN(C)CC2)c1
Reaction time: 19 h
Yield: 16 %

Procedure:
A suspension of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.92 g) and methyl 3-amino-4-methoxybenzoate (1.81 g) in n-butanol was refluxed with stirring for 19 h. Anhydrous sodium carbonate (0.54 g) was added and refluxing continued for 8.5 h. The solvent was then removed to give an oil which was taken up in water (50 ml) and 2N hydrochloric acid (50 ml) and extracted with ethyl acetate (2×50 ml). The acid solution was then basified with sodium bicarbonate and re-extracted with ethyl acetate (3×50 ml). The extracts were dried and concentrated to a semi-solid (2.47 g) which was absorbed from System A (200:8:1) (5 ml) onto Kieselgel G (100 g). Elution with the same solvent gave starting material and minor basic impurities. Further elution with System A (100:8:1) (450 ml) gave first minor impurities and later fractions afforded the free base of the desired product as a gum (0.48 g). This was taken up in methanol (5 ml), filtered and treated with ethereal hydrogen chloride and diluted to 25 ml with ethyl acetate. A cream coloured solid separated and was collected giving the title compound (0.586 g), m.p. 190°-194°. Recrystallisation from methanol-ethyl acetate afforded a sample for analysis.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][S:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[Cl:24])[CH:20]([C:25](Cl)=[O:26])[CH2:19][C:18]2=[O:28]>C(N(CC)CC)C>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[Cl:24])[CH:20]([C:25]([N:9]1[CH2:10][CH2:11][S:12][CH2:13][CH:8]1[CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:26])[CH2:19][C:18]2=[O:28]
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: C1CCN(CC2CSCCN2)CC1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCSCC2CN2CCCCC2)c2cc(Cl)c(Cl)cc21
Yield: 34.1 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.9 g of 3-(piperidinomethyl)thiomorpholine, 1.0 g of triethylamine and 1.5 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride, to afford 0.45 g of the title compound, melting at 146°-155° C.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:17][CH:16]=1>>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:30]([C:29]3[CH:28]=[CH:27][C:26]([C:23]4[S:24][CH:25]=[C:21]([C:18]5[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=5)[N:22]=4)=[CH:34][CH:33]=3)=[O:31])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)cs2)cc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Product: O=C(c1ccc(-c2nc(-c3ccc(F)cc3)cs2)cc1)N1CCCN(C2CCC2)CC1

Procedure:
The title compound (E8) was prepared from 1-(cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) and 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]benzoic acid using the procedure described in Example 7. MS APCl 436 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:21]([NH:20][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[O:10])=[O:22])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
To a stirring solution of 5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide (0.48 g, 0.96 mmol) in methanol (20 mL),was added sodium borohydride (36 mg, 0.96 mmol). The reaction was stirred at room temperature for 5 min, treated with water, and concentrated in vacuo. The residual mixture was partitioned between ethyl acetate and water and the layers separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.47 g (98%) of a white foam.