Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9](=[O:12])[NH:10][N:11]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9](=[O:12])[N:10]([CH2:22][C:23]#[N:24])[N:11]=2)=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=c1[nH]nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O

Procedure:
A mixture of 250 mg (0.81 mmol) of 5-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 154A], 67 μl (0.97 mmol) of bromoacetonitrile and 223 mg (1.61 mmol) of potassium carbonate was stirred in 8 ml of dry DMF at an oil bath temperature of 100° C. for 1 h. After cooling, the mixture was filtered through kieselguhr, the filtrate was concentrated under reduced pressure and the residue was partitioned between MTBE and water. The organic phase was washed successively with 10 ml of water and 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 258 mg (92% of theory) of the target compound as a slightly yellowish solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:18]1=[O:33])[CH3:16].[H-].[Na+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=4[N:4]=3)=[CH:30][CH:31]=2)[C:18]1=[O:33])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2c1CCCC2
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(-c2ccc(Oc3nc4c(n3C)CCCC4)cc2)c2ncccc21
Yield: 5.8 %

Procedure:
1-Methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (84 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (18.8 mg) (60% in mineral oil) in DMA (3 mL) in a microwave vessel. The vessel was sealed and subjected to microwave irradiation (at 120° C. set by IR sensor, fixed hold time: on, Absorption level: High) for 1 h in a Biotage Initiator 60EXP. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20%-100% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8.90 mg) as white crystals.
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:28])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:7]2[C:8]([OH:21])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:6]=2[O:5]1.[CH3:29]N(C)C=O.C[O-].[Na+]>O>[CH3:28][C:4]1([CH3:3])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:7]2[C:8]([O:21][CH3:29])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:6]=2[O:5]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (5.11 g., 0.036 mole) was added dropwise to a stirred solution of 10.59 g. (0.03 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano [3,4-d]pyridine in 300 ml. of N,N-dimethylformamide containing 1.78 g. (0.033 mole) of sodium methoxide. The mixture was stirred at room temperature for 18 hours and 300 ml. of water was added and extracted with petroleum ether (30°-60°). The combined petroleum ether extracts were washed with water, dried with anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on a Florisil® column with chloroform or by distillation under reduced pressure to give the pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=1)[C:9]1[N:20]2[C:16](=[CH:17][CH:18]=[N:19]2)[N:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][N:13]2[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:45]N1C(=O)CCC1=O>C1COCC1>[I:45][C:17]1[CH:18]=[N:19][N:20]2[C:16]=1[N:15]=[C:14]1[C:10]([CH2:11][CH2:12][N:13]1[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=1
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4c(I)cnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a THF solution (1.5 mL) of tert-butyl (S)-3-(8-[tert-butoxycarbonyl-{4-(2-methoxyethoxy)phenyl}amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (110.6 mg, 0.182 mmol), N-iodosuccinimide (49.1 mg, 0.218 mmol) was added at room temperature and the mixture was stirred for 3 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was removed under reduced pressure and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (118.9 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:12]([CH2:11][CH2:10][OH:14])=[CH:13][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)OC(C)C
Product: OCCc1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 72.2 %

Procedure:
The product from Example 3A (14.95 g, 50 mmol), palladium(ll) acetate (0.11 g, 0.5 mmol), triphenylphosphine (0.26 g, 1.0 mmol), and copper(I) iodide (0.19 g, 1.0 mmol) were combined in isopropyl acetate (100 mL). Nitrogen gas was bubbled through the reaction mixture for about 15 minutes. The mixture was treated with 3-butyn-1-ol (5.6 mL, 75.0 mmol) stirred briefly and then treated with diisopropylamine (42 mL, 300 mmol) slowly over about 10 minutes. After stirring for 2 hours at about 22° C., the mixture was heated at about 60° C. for about 6 hours and then cooled to about 22° C. The reaction mixture was filtered through a pad of Celite® (˜5 g) and the Celite® was washed with isopropyl acetate (˜30 mL). The filtrate was washed with saturated NaHCO3 solution (100 mL, 2×), 10% Na2S2O3 solution (100 mL, 2×), brine (50 mL), dried over Na2SO4, and distilled to dryness. The residue was purified by silica gel column chromatography to provide the title compound (8.7 g, 72% yield). MS DCl (M+NH4)+ m/z at 258,260; 1H NMR(CDCl3at 400 MHz) δ 3.03 (m, 2H), 3.98 (m, 2H), 6.45 (m, 1H), 7.25-7.32 (m, 2H), 7.60 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 32.2, 60.6, 103.0, 112.1, 115.4, 122.8, 126.1, 130.4, 153.1, 157.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19].O1CCCC1.[H][H]>[Rh].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19]
Reactant: COC(=O)C=Cc1cc(Cl)ccc1OCCCCCBr
Reactant: [H][H]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Yield: 100.8 %

Procedure:
A mixture of 2.02 g (5.59 mmol) of 3-[2-[(5-bromopentyl)oxy]-5-chlorophenyl]-2-propenoic acid methyl ester (mixture of E/Z isomers), 90 mL of tetrahydrofuran, 190 mL of toluene, and 1.26 g of 5% rhodium on alumina was stirred at room temperature, in an atmosphere of hydrogen, until reduction was complete. The catalyst was removed by suction filtration and the filtrate was concentrated in vacuo giving 2.05 g (ca. 100%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester as a pale-yellow oil which was used without further purification.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:2]1[C:1]2([CH2:6][CH2:12][C:10](=[O:11])[CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=CC1CCCC1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCCC2)CC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of cyclopentanecarbaldehyde (10 g, 100 mmol) in toluene (100 mL) were added methyl vinyl ketone (7.8 g, 110 mmol) and p-toluenesulfonic acid (1.9 g, 10 mmol), and the mixture was stirred at 120° C. for 3 hours, using a Dean-Stark apparatus to remove water. The reaction mixture was air-cooled to room temperature, then saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 6.0 g of the title compound as a red oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11]4[N:12]([CH:14]=[CH:15][CH:16]=4)[CH:13]=3)=[CH:4][CH:3]=2)[CH:29]=[N:28]1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(-c2ccc(-c3cnn(CCOC4CCCCO4)c3)cc2)cn2cccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
Under nitrogen, a suspension of 145 mg (0.50 mmol) 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one, 177 mg (0.55 mmol) 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 50 mg (0.60 mmol) sodium hydrogen carbonate in 1 ml DMF and 0.5 ml water is heated to 40° C. Then 7.0 mg (0.010 mmol) bis(triphenylphosphine)palladium(II)-chloride is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 3-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.39 min (B), [M+H] 405;
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1>O1CCCC1>[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=3)=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(-n3ccnc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5.0 g of p-tetradecyloxyphenylacetyl chloride in 50 ml of tetrahydrofuran is added to a solution of 4.31 g of pyridine and 2.36 g of 4-(2-methyl-1H-imidazol-1-yl)benzenamine in 50 ml of tetrahydrofuran over 5 minutes. The mixture is stirred at ambient temperature for 1 hour, heated to reflux and allowed to stir at room temperature for 2 hours. The solvent is evaporated to a residue which is partitioned between chloroform and dilute sodium bicarbonate. The organic layer is separated, washed with water, dried and filtered through a pad of magnesium silicate. The solvent is evaporated to an oil which crystallizes from methyl alcohol:water to give 4.0 g of white solid which is chromatographed on silica gel using ethyl acetate containing 0.1% ammonium hydroxide to give 3.9 g of the desired product as a white solid, m.p. 106°-109° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[N:9]=[N:10][CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[I:20]N1C(C)(C)C(=O)N(I)C1=O>>[I:20][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[N:6]=[CH:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:8]=3[N:9]=[N:10][CH:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1
Product: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1I
Yield: 79 %

Procedure:
Prepared by a Method analogous to that as described above for Preparation 87 using 7-cyclopropyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 93) and 1,3-diiodo-5,5-dimethylhydantoin to afford the title compound in 79% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCCCCOCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCc2ccccn2)cc1

Procedure:
2-[2-[(6-Bromohexyl)oxy]ethyl]pyridine (6.3 g) was added to benzylamine (20 ml) at 140° under nitrogen. After 1 h at 140° the reaction mixture was cooled and partitioned between 2M sodium hydroxyde (100 ml) and ether (100 ml). The organic layer was washed with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation under reduced pressure to leave the title compound as a yellow oil (6.8 g), t.l.c. (System A 80:20:2) Rf 0.44.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:10]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCBr)OCc1ccccc1

Procedure:
A mixture of 6-bromo-hexanoic acid (0.10 mol), benzyl alcohol (0.10 mol), 4-dimethylaminopyridine (1.78·10−2 mol) and dichloromethane (600 ml) is stirred and kept at 0° C. with an ice bath, then added with N,N′-dicyclohexylcarbodiimide (0.13 mol) and left to react for 16 hours. At the end of the reaction, the solution is filtered and the precipitate is discarded, whilst the solution is repeatedly washed with H2O, discarding the precipitate possibly formed. The organic layers are pooled and washed again with a saturated solution of NaHCO3, a solution of HCl 0.1 M and then with water. The solution is dried with MgSO4, filtered, and the solvent is removed by vacuum evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CO)c(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1ccc(-c2ccccc2C#N)cc1Br)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a solution of 670 mg (2.35 mmol) of 3'-bromo-4'-hydroxymethyl-1,1'-biphenyl-2-nitrile (Step F) in 5 mL of dry dimethylformamide under a nitrogen atmosphere was added 237 mg (3.49 mmol) of imidazole. The reaction mixture was cooled to 0° C. and 0.73 mL (2.8 mmol) of t-butylchlorodiphenylsilane was added dropwise by syringe over 5 minutes. The resulting solution was stirred at 0° C. for 15 minutes then at room temperature for 2 hours. The reaction mixture was poured into 100 mL of water and extracted with ether (3×75 mL). The combined ether extracts were washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to afford 1.24 g (100%) of the product as a clear oil. 1H NMR (200 MHz, CDCl3): δ 1.13 (s, 3H), 4.80 (s, 2H), 7.30-7.50 (m, 9H), 7.55-7.80 (m, 7H), 7.86 (d, 8 Hz, 1H). FAB-MS: calculated for C30H28BrNOSi 526; found 527, 528, 271 (60%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)O1>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([C:2]3[CH2:6][CH2:5][C:4](=[O:7])[C:3]=3[CH3:8])=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: CC1=C(Br)CCC1=O
Product: CC1=C(c2ccc3[nH]ccc3c2)CCC1=O
Yield: 92 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 100% ethyl acetate/hexanes) and further recrystallization yielded the product (138 mg, 92%) as pale yellow solid. 1H NMR (CDCl3, 300 MHz): δ 7.86 (s, 1H), 7.47-7.39 (m, 2H), 7.27 (t, J=3.0 Hz, 1H), 6.62 (t, J=2.1 Hz, 1H), 3.02-2.97 (m, 2H), 2.57-2.54 (m, 2H), 2.05 (t, 3H, J=1.8). 13C NMR (CDCl3, 75 MHz): δ 210.0, 168.3, 136.2, 134.5, 128.2, 127.8, 125.3, 121.9, 120.6, 111.1, 103.4, 34.2, 29.7, 10.5. LCMS (ESI): mass calcd for (C14H13NO) m/z 211.10; measured [M+H]+: m/z 212.03.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C)CCN(C)C.C([Li])CCC.CN([CH:33]=[O:34])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:33]=[O:34])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.0 g, 3.91 mmol) in anhydrous THF (50 mL) was added N,N,N′,N′-tetramethylethylenediamine (0.68 mL, 4.53 mmol) and the resulting mixture was cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 1.9 mL, 4.75 mmol) was added dropwise and the resulting suspension allowed to warm to −30° C. over 1 h. The reaction mixture was cooled to −78° C. and treated with DMF (0.7 mL, 9.04 mmol), then stirred at RT for 30 min. The reaction mixture was cooled to 0° C. before an aqueous solution of HCl (0.5 M) was added and the mixture stirred for another 30 min. The precipitate that formed was collected by filtration, washed twice with water then dried in vacuo at 70° C. for 3 h. The title compound was obtained as a pale yellow solid (1.0 g 90%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:32][CH2:33]Cl)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[CH2:32][CH2:33]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: FC(F)(F)c1ccc(CN(CCCl)CCCl)cc1
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Yield: 54.4 %

Procedure:
A solution of 4.2 g (16.5 mmol) of methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.95 g (16.5 mmol) of bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine in 25 ml of N,N-diisopropylethylamine is heated at 127° C. for 6 h. After evaporation of a maximum amount of diisopropylethylamine, the reaction medium is diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide having a concentration of 1N. The organic phase obtained is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 4.0 g (55%) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.I[CH2:19][CH:20]([CH3:22])[CH3:21]>>[CH3:15][O:14][C:12]([C:10]1[CH:11]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=[C:5]2[C:9]=1[N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:7]=[CH:6]2)=[O:13]
Reactant: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Reactant: CC(C)CI
Product: COC(=O)c1cc(C(F)(F)F)cc2cnn(CC(C)C)c12
Yield: 39 %

Procedure:
Compound 12 was prepared following general method 1, using compound 4 as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 39%.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.O.[NH2:12][NH2:13]>C(O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:12][NH2:13])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: COc1ncc(Br)nc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ncc(Br)nc1NN
Temperature: 80 °C

Procedure:
A 100 mL round bottom flask was charged with 3,5-dibromo-2-methoxypyrazine (0.50 g, 1.9 mmol), hydrazine hydrate (0.47 g, 9.4 mmol) and ethanol (5 mL). The resulting mixture was heated at 80° C. for 4 h. TLC indicated a complete conversion. Work-up: the reaction solution was concentrated in vacuo, to afford 0.5 g (crude) of the product as a brown solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:18]([N:21]([CH3:23])[CH3:22])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[CH:8][C:9]=1[N:10]=[CH:18][N:21]([CH3:23])[CH3:22])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(C(=O)C(C)C)cc1N
Product: COC(=O)c1sc(C(=O)C(C)C)cc1N=CN(C)C

Procedure:
3-Amino-5-isobutyrylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 382.36 (C13H18N2O3S) was obtained in this way; MS (ESI): 383 (M+H+).