Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:36]CC2C=CC=CC=2)=[C:16]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])=[C:24]([CH3:35])[CH:23]=2)=[O:20])[CH:17]=1)=[NH:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[H][H].[Pd]>[C:1]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:36])=[C:16]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:29])=[C:24]([CH3:35])[CH:23]=2)=[O:20])[CH:17]=1)=[NH:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Agent: [Pd]
Product: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2O)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 5h from 2-[5-(N-benzoyl-carbamimidoyl)-2-benzyloxy-phenyl]-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetamide and hydrogen/palladium on activated charcoal.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:14](=[O:24])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37](C(O)=O)=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:6]([N:8]4[CH2:11][CH:10]([N:12]5[CH2:17][CH2:16][N:15]([C:18]6[N:19]=[CH:20][CH:21]=[CH:22][N:23]=6)[C:14](=[O:24])[CH2:13]5)[CH2:9]4)=[O:5])=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Product: O=C(c1ccc2c(ccn2-c2ccc(F)cc2)c1)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1

Procedure:
Cpd 4 was prepared according to the procedures described in Example 2, Step D, using intermediates 3c and 1-(4-fluoro-phenyl)-1H-indole-5-carboxylic acid 3h as starting materials. MS 471 (M+H+).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].Cl.Cl[CH2:18][C:19]1[N:23]([CH2:24][CH2:25][CH3:26])[CH:22]=[N:21][CH:20]=1>C(O)C>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH2:18][C:19]3[N:23]([CH2:24][CH2:25][CH3:26])[CH:22]=[N:21][CH:20]=3)[NH:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2nc(S)[nH]c2c1
Reactant: CCCn1cncc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1cncc1CSc1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
2-mercapto-5-nitrobenzimidazole (2.0 g) was dissolved in ethanol (20 ml), 3N sodium hydroxide (8.2 ml) was added to the mixture, 5-chloromethyl-1-propylimidazole hydrochloride (2.2 g) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and to the obtained residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-5-yl)methyl]thio]benzimidazole (1.6 g).
Reaction SMILES: [Br:1][C:2]1([N+:25]([O-:27])=[O:26])[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[CH:4][CH:3]1[OH:24].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31].BrBr>>[Br:1][C:2]1([N+:25]([O-:27])=[O:26])[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[CH:4][CH:3]1[O:24][CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(O)C=C3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Product: Cc1sc2c(Br)c3ccccc3c(C3=CC(Br)([N+](=O)[O-])C(OC(Cc4ccccc4)C(=O)O)C=C3)c2c1C

Procedure:
Prepared from of 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (Example 21) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: mp 243-245° C.: NMR (DMSO-d6); δ11.30 (broad s, 1H), 8.23, 8.22 (2d, J=3 Hz, 1H), 8.06, 8.04 (2d, J=3 Hz, 1H), 7.95 (t, J=2, 1H), 7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.45 (d, J=8 Hz, 1H),7.34-7.24 (m, 6H), 5.28 5.22 (2t, J=6 Hz, 1H), 3.40-3.23 (m, 2H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.59 1.57 (2s, 3H); MS (+FAB): 2 bromine isotope pattern 653, 655 , 657; Anal. Calc. for C29H21Br2NO5S: C, 53.15; H, 3.23; N, 2.14. Found: C, 53.77; H, 3.73; N, 2.04.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]1OC(=O)C)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].O>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C1CCC=CC1OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)C1=CC=CCC1
Yield: 85.4 %

Procedure:
Crude butyl ester (a) (55.25 g, max 0.207 mol) was dissolved in dry tetrahydrofuran (320 ml) and cooled in an ice/salt bath. To this was added slowly, over 1 hour, potassium t-butoxide in tetrahydrofuran (1 M, 220 ml, 0.22 mol). After 0.5 hour water and petroleum ether were added and the mixture filtered quickly through kieselguhr. The phases were separated and the aqueous extracted with more petroleum ether (×2). The combined organic extracts were washed with brine, dried and evaporated to give a mobile orange oil (31.85 g, 86%), which was used immediately without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:14])[CH2:6][C:7]2=[O:13].CCN(CC)CC.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH2:4][CH:5]([CH3:14])[CH2:6][C:7](=[O:13])[C:8]=2[C:9]([O:12][S:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: CC1CC(=O)c2c(O)ccc(Br)c2C1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC(=O)c2c(OS(=O)(=O)c3cccs3)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
To a solution of 5-bromo-8-hydroxy-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (Intermediate 1, Step 1) (0.2 g, 0.78 mmol) in DCM (10 mL) was added Et3N (1.1 mL, 7.8 mmol) and thiophene-2-sulphonyl chloride (0.57 g, 3.1 mmol). This mixture was stirred at room temperature for 5 h, and then partitioned with DCM (20 mL) and water (20 mL). The two phases were separated and the aqueous phase extracted with DCM (20 mL). The combined organic phases were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel eluting with EtOAc:hexane (10:90-35:65) to afford the title compound (0.24 g, 75%) as an orange solid. mp 110-113° C. 1H NMR (360 MHz, CDCl3) δ 1.14(3H,d, J=6.0 Hz), 2.10-2.30(2H,m), 2.48-2.62(2H,m) 3.16-3.22(1H,m), 7.02(1H,d, J=8.7 Hz), 7.14(1H,dd, J=3.8, 4.9 Hz), 7.69-7.76(3H,m). MS(ES+) 401/403 (M+1).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:42][C:43]([N:45]1[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]1([CH3:54])[CH3:53])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]2([CH3:54])[CH3:53])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 6.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.4 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[N:18]1([C:23]2[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[C:23]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:24][C:25]([C:34]([F:37])([F:35])[F:36])=[CH:26][CH:27]=1)#[CH:17]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1N1CCCC1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCCC2)cc(F)c1NS(C)(=O)=O
Yield: 79.2 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (94 mg, 0.327 mmol) was reacted with 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (78 mg, 0.272 mmol) to give the title compound (110 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:21]CC4C=CC=CC=4)=[C:17]([Cl:20])[CH:18]=3)[C:13]([C:29]#[N:30])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([Cl:20])[CH:18]=3)[C:13]([C:29]#[N:30])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OCc4ccccc4)c(Cl)cc32)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(O)c(Cl)cc32)cc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 4-(5-benzyloxy-6-chloro-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.310 g) in dichloromethane (7 mL) was added boron tribromide (1 mol/L dichloromethane solution) (0.860 mL) under ice cooling, and this mixture was stirred at the same temperature for 1 hour. To this reaction mixture was added water, this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. This filtrate was removed under reduced pressure. The residue was washed with diethyl ether to give the title compound (0.181 g).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]3[CH2:24][CH2:23]3)[C:17]=2[F:25])=[CH:12][C:11]1=[O:26])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[CH:22]1([C:18]2[C:17]([F:25])=[C:16]([CH:21]=[CH:20][CH:19]=2)[O:15][C:13]2[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:27])=[O:3])[C:11](=[O:26])[CH:12]=2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C3CC3)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C3CC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To a solution containing (S)-2-[4-(3-cyclopropyl-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.800 g, 0.002 mol) in tetrahydrofuran (30 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 15 mL, 0.008 mol). The mixture was stirred at room temperature for 1 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-cyclopropyl-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.71 g, 96%) as a yellow solid.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH:5]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH:5]=[C:4]1[CH2:3][CH2:2][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ICCC1=COc2ccccc2O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC1=COc2ccccc2O1
Temperature: 60 °C

Procedure:
1 g (3.47 mmol) of the iodinated compound obtained in Step D and 0.964 g (5.2 mmol) of potassium phthalimide are dissolved in 20 ml of anhydrous N,N-dimethylformamide; the reaction mixture is then heated at 60° C. for 22 hours under argon. After cooling of the mixture, the solvent is evaporated in vacuo; the residue is then taken up in ethyl acetate. After washing with water and extraction of the aqueous phase with ethyl acetate, the organic phases are dried over magnesium sulphate. The solvent is then evaporated in vacuo; the title phthalimide is then obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 30/70).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of Example 21 step a (0.41 g, 2.08 mmol), triphenylphosphine (763 mg, 2.91 mmol) and triethylamine (0.87 mL, 6.24 mmol) in THF (5 mL) at 0° C. was treated with 1,2-hexachloroethane (690 mg, 2.91 mmol). The reaction mixture was stirred at 0° C. for 40 min then at RT for 20 min, quenched with water, extracted twice with EtOAc, dried (Na2SO4), evaporated and purified twice by FCC (cyclohexane/EtOAc 1/0 to 1/1) to afford the title compound (274 mg, contaminated with 20% PPh3O, 58%) as a white solid. LCMS (Method 5): Rt 2.58 min, m/z 180 [MH+].
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:20][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1CCN(Cc2ccccc2)CCN1
Temperature: 5 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Concentrated sulfuric acid (25 mL) was added to 1-benzyl-4-piperidone (10.14 g) in acetic acid (50 mL) at room temperature, and sodium azide (3.880 g) was added thereto at 0° C. over a period of 2 hours, followed by stirring at 5° C. for 25 hours. The reaction mixture was alkalinized through addition of aqueous sodium hydroxide, followed by partitioning by use of chloroform. The aqueous layer was extracted with chloroform. The organic layers were combined, and washed with saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and then the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (5.081 g, 47%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH2:15]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:15][CH:14]=[CH:13][C:12]3[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: ClCC=Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(OCc3ccccc3)cc1)CC2
Yield: 13 %

Procedure:
Prepared from 4-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform for one hour at 50° C. Yield: 13% of theory, Melting point: 135°-140° C. (ether).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a solution of 4-iodoimidazole (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 hours, the solution was poured into ice water and left stirring for 30 minutes. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-Iodo-1-trityl-1H-imidazole (92%) as a white solid. MH+(437).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)C(C)(C)C)cs2)ccc1-n1cnc(C)c1
Yield: 98.8 %

Procedure:
96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 25 mg (0.2 mmol) pivaloylchloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 90 mg (99%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-2,2-dimethyl-propionamide as a light yellow solid. MS ISP (m/e): 456.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.37 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.22 (d, 1H), 7.05-6.99 (m, 2H), 6.44 (s, 1H), 4.95 (m, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.73 (m, 2H), 1.65 (m, 1H), 1.14 (s, 9H), 0.91 (d, 3H), 0.87 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.O1CCOC[CH2:20]1>>[CH3:1][C:2]1[N:3]([CH3:20])[C:4](=[N:17][CH3:18])[C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: C1COCCO1
Reactant: CNc1nc(C)nc2c1ccn2-c1ccccc1
Product: CN=c1c2ccn(-c3ccccc3)c2nc(C)n1C

Procedure:
A mixture of 2-methyl-4-methylamino-7-phenyl-7H-pyrrolo-[2,3-d] pyrimidine (0.5g, 2.1mM) and dioxan (15ml) was heated under reflux for 18 hours. The mixture was cooled and then the solvent was removed by evaporation. The residue was purified by flash chromatography on ICN neutral alumina (32-63) using methylene chloride which contained an increasing amount of methanol (up to a maximum of 5%) as eluant to give a solid. This solid was recrystallised from hexane to give 2,3-dimethyl-4-methylimino-7-phenyl-3H,7H-pyrrolo[2,3-d] pyrimidine as a white solid (126mg), m p. 160-161° C; microanalysis, found: C, 71 2; H,5 9; N,22.0%; C14H14N4 requires C,71.4; H, 6.3; N, 22.2%; NMR: 2.48(3H,s,C-CH3), 3.48 (3H,s,N-CH3), 3.56(3H,s,N-CH3), 6.90(1H,d,CH), 6.97(1H,d,CH), 7.34(1H, complex, aromatic), 7.47(2H, complex, aromatic), 7.60(1H, complex, aromatic).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:42][CH:41]=4)=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:42][CH:41]=4)=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)OC(C)(C)C)C4)cc3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)O)C4)cc3)nc2)cc1
Reaction time: 4 h
Yield: 97.2 %

Procedure:
Prepared using General Procedure 8: To a stirred solution of tert-butyl (S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (188 mg, 0.26 mmol), in DCM (2 mL) was added TFA (2 mL). The mixture was stirred for 4 h then concentrated. The resulting solid was dissolved in DCM (10 mL) and concentrated (5×) to remove excess TFA, affording 169 mg (98%) of 1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid 798 as a yellow solid. LCMS-ESI (m/z) calculated for C38H44N4O5S: 668.85. found 669.3 [M+H]+, tR=9.121 min (Method 16). 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 2H), 8.12 (d, J=7.8 Hz, 2H), 7.58 (m, 3H), 7.45 (m, 1H), 7.42 (m, 2H), 7.06 (m, 2H), 6.84 (m, 1H), 4.71 (d, J=7.7 Hz, 1H), 4.33-4.14 (m, 2H), 4.08 (dd, J=19.8, 9.1 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 3.30 (dd, J=12.5, 4.2 Hz, 1H), 3.06 (t, J=11.9 Hz, 1H), 2.91 (s, 1H), 1.91-1.76 (m, 2H), 1.64 (dt, J=13.0, 6.6 Hz, 1H), 1.43-1.33 (m, 11H), 0.95 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Mg].[CH2:12]1[O:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:12][CH2:13][OH:14])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCSc1ccc(Br)cc1
Reactant: C1CO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
1-Bromo-4-(ethylthio)benzene (16.0 g) in THF (80 ml) was added dropwise to magnesium (1.82 g) to maintain gentle reflux. The resulting cloudy solution was cooled to 0° and ethylene oxide (6.6 g) in THF (10 ml) was added dropwise. The mixture was stirred at room temperature for 30 min and at reflux for 1 h. Saturated aqueous ammonium chloride (200 ml) was added and the mixture was extracted with ER (2×200 ml). The dried extracted was evaporated and the residue was purified by [C] eluting with cyclohexane-ER (7.3) to give the title alcohol (2.15 g). T.l.c. (cyclohexane-ER 1:1) Rf 0.4.