Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Product: CCCS(=O)(=O)NCCOc1nc(-c2ccccn2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 100 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 1-propanesulfonylchloride to give 76 mg 5-isopropyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.56 min, [M+1]+=643.65, [M−1]−=641.70.
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][N:9]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]=3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH3:28]
Reactant: c1ccc2c(c1)ccc1[nH]c3ccccc3c12
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)Cn1c2ccccc2c2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7H-benzo[c]carbazole (0.78 g, 3.59 mmol) in dimethylformamide (DMF) (4 ml) is added sodium hydride (0.21 g, 5.21 mmol) at 0° C., and the mixture is stirred for 1 hour. To the reaction mixture is added 1-bromo-2-ethylhexane (1.04 g, 5.39 mmol). The mixture is stirred at room temperature overnight, and then at 0° C. for 5 hours. After the reaction mixture is cooled at room temperature, it is poured into ice-water, and the crude product is extracted with AcOEt, and washed with water and brine. After drying over MgSO4 and concentration, the desired product is obtained as a brown liquid (1.21 g, 99%). The structure is confirmed by 1H-NMR spectrum (CDCl3) δ [ppm]: 0.83-0.92 (m), 1.20-1.43 (m), 2.07-2.10 (m), 4.24-4.38 (m), 7.37 (td), 7.44-7.50 (m), 7.52-7.54 (m), 7.62 (d), 7.69 (td), 7.87 (d), 7.99 (d), 8.59 (d), 8.80 (d)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[N:12](C(O[C@@H]3C[C@H](C)CC[C@H]3C(C)(C3C=CC=CC=3)C)=O)[C:11]3[CH2:39][O:40][CH2:41][C:42](=[O:43])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].C[O-].[Na+]>CO.C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][C:13]=3[NH:12][C:11]3[CH2:39][O:40][CH2:41][C:42](=[O:43])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2C3=C(C(=O)COC3)C(c3ccc(F)c(Br)c3)C3=C2CCS3(=O)=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCS1(=O)=O)N2
Reaction time: 16 h
Yield: 62.1 %

Procedure:
A solution of Example 12A (0.98 g, 1.4 mmol) in methanol/methylene chloride (40 mL/10 mL) was degassed with nitrogen, treated with of 25% sodium methoxide in methanol (30 drops), stirred for 16 hours, filtered, and concentrated to a volume of 5 mL of methanol. The solid which had precipitated was collected by filtration, washed with methanol and dried under vacuum for 16 hours to provide the title compound (0.36 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH2:8][C@@H:9]2[C@@H:25]([C@:26]3([CH3:33])[C:31]=1[CH2:30][C@@H:29]([OH:32])[CH2:28][CH2:27]3)[CH2:24][CH2:23][C@@:22]1([CH3:34])[C@H:10]2[CH2:11][CH2:12][C@@H:13]1[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:4][CH3:5])[CH3:2].N1C=CC=CC=1.[C:41](Cl)(=[O:44])[CH2:42][CH3:43].C(=O)(O)[O-].[K+]>O>[CH2:4]([N:3]([CH2:6][C:7]1[CH2:8][C@@H:9]2[C@@H:25]([C@:26]3([CH3:33])[C:31]=1[CH2:30][C@@H:29]([O:32][C:41](=[O:44])[CH2:42][CH3:43])[CH2:28][CH2:27]3)[CH2:24][CH2:23][C@@:22]1([CH3:34])[C@H:10]2[CH2:11][CH2:12][C@@H:13]1[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)CC1=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)O[C@H]1CC[C@@]2(C)C(=C(CN(CC)CC)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 2 h

Procedure:
To a solution of 10 parts of 6-(diethylaminomethyl)cholest-5-en-3β-ol in 40 parts of pyridine at 0° is added, slowly and with stirring, 5 parts of propionyl chloride. When the addition is complete, stirring is continued for 2 hours while the reaction mixture warms to room temperature, whereupon 100 parts of water and 100 parts of aqueous 5% potassium bicarbonate are consecutively mixed in. The oil which separates is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation, affording 6-(diethylaminomethyl)-3β-(propionyloxy)cholest-5-ene as the residue.
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH:6][C:7](=[O:15])[CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[F:16][C:17]1[CH:31]=[CH:30][C:20]([CH:21](Cl)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:12]2[CH2:13][CH2:14][C:9](=[CH:8][C:7]([NH:6][CH2:5][CH:2]3[CH2:4][CH2:3]3)=[O:15])[CH2:10][CH2:11]2)=[CH:30][CH:31]=1
Reactant: O=C(C=C1CCNCC1)NCC1CC1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(C=C1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCC1CC1
Yield: 77.8 %

Procedure:
A mixture of N-(cyclopropylmethyl)-2-(piperidin-4-ylidene)acetamide hydrochloride (80.0 mg, 0.347 mmol) prepared in EXAMPLE 22e, 4,4′-difluorobenzhydryl chloride (0.105 ml, 0.555 mmol), K2CO3 (105 mg, 0.763 mmol) and KI (5.8 mg, 0.035 mmol) in acetonitrile (5 ml) was stirred under reflux for 12 hours. The reaction was quenched with H2O (20 ml), extracted with chloroform (30 ml×2), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane:30/70 to 50/50) to give 2-(1-(bis(4-fluorophenyl)methyl)piperidin-4-ylidene)-N-(cyclopropylmethyl)acetamide (107 mg, 78%) as a white solid: LCMS: 397 {M+1}+. 1H NMR (DMSO-d6)□ δ: 0.11 (m, 2H), 0.38 (m, 2H), 0.87 (m, 1H), 2.22 (m, 2H), 2.32 (m, 2H), 2.36 (m, 2H), 2.93 (m, 4H), 4.47 (s, 1H), 5.61 (s, 1H), 7.13 (m, 4H), 7.43 (m, 4H), 7.87 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.CN(C=O)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
8-Chloro-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (2.0 g, 9.3 mmol) was dissolved in DMF (50 ml) K2CO3 (2.57 g, 18.6 mmol) and benzyl bromide (1.75 g, 10.3 mmol) were added and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was evaporated in vacuo the residue was dissolved in DCM:H2O (1:1) (100 ml) the water phase was extracted with DCM (50 ml) the combined organic phase was dried with MgSO4 filtered and evaporation gave 4A as a white crystalline compound. Yield: 2.92 g. Mp: 145.7–147.1° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][CH2:23][CH3:24].[CH3:25][CH:26]([S-:28])[CH3:27].[Na+]>CN(C=O)C>[CH3:25][CH:26]([S:28][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][CH2:23][CH3:24])[CH3:27]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCCl
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCSC(C)C
Temperature: 25 °C
Yield: 84 %

Procedure:
Nitrogen was bubbled through a solution of 1-[2-(3-chloropropoxy)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 7.21 mmol) in DMF (25 mL) for 5 minutes. Sodium 2-propanethiolate (0.85 g 8.65 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere at ambient temperature. After 16 hours analysis by HPLC indicated that 50% of the starting material had been consumed. Additional sodium 2-propanethiolate (0.6 g) was added followed by a second addition (0.25 g) 2.5 hours later. After a total of 21 hours the reaction mixture was poured into water (250 mL) with rapid stirring. The resulting tan precipitate was isolated by filtration to provide 2.34 g of 1-(2-{3-[(1-methylethyl)thio]propoxy}ethyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)C)=[CH:23][C:11]=3[C:12](=[O:22])[C:13]=2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[ClH:31]>C(Cl)(Cl)Cl.CO>[ClH:31].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:11]=3[C:12](=[O:22])[C:13]=2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(OCc3ccccc3)c(=O)c2c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1ccc2oc(-c3ccc(O)cc3)c(OCc3ccccc3)c(=O)c2c1
Yield: 82 %

Procedure:
Prepared analogously to Example 5c, starting from 2-(4-hydroxyphenyl)-3-benzyloxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 82%; TLC (9/1 Chloroform/Methanol) Rf: 0.71 Elem. anal. C29H23NO4*HCl; theory C, 71.68; H, 4.98; N, 2.88. found C, 71.35; H, 4.76; N, 3.03. 1H-NMR (d6-DMSO): 8.02 (d, 2H), 7.8-7.7 (m, 2H), 7.55-7.25 (m, 11H), 7.18 (d, 2H), 5.22 (s, 2H), 5.08 (s, 2H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1>>[CH3:43][C:39]1([CH3:44])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]2[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]3[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=3)[CH:42]=[CH:41][C:40]1=2
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: CC1(C)CCC(C)(C)c2cc(/C(=C/c3ccc(CO)cc3)[Si](C)(C)C)ccc21

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether (Compound 2, 0.89 g, 2.0 mmol) and 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (0.60 g, 2.25 mmol) were coupled to give the title compound. 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene can be prepared in accordance with the procedure set forth in J. Med. Chem. 37:293041 (1994). The pentamethyl derivative thereof can be prepared in accordance with the same procedure.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C@@H:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>CN(C=O)C>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH2:15][O:14][CH2:13][C@@H:12]([NH:11][CH2:2][C:3]#[N:4])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=1
Reactant: N#CCBr
Reactant: N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 1.5 h

Procedure:
Bromoacetonitrile (570 μl) was stirred in a 0.5M solution of anhydrous DMF (15ml) at 60° C. with potassium carbonate (2.07g) for 5 minutes before (S)-2-amino-1-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylethane (2.7g, Example 2b, liberated from the salt by extraction into ethyl acetate from aqueous Na2CO3 solution) was added. After 1.5 hours, the solution was cooled and the reaction quenched with water (100ml) and diluted with Ethyl acetate (60ml). The mixture was separated and the aqueous layer further extracted with ethyl acetate (4×30ml). The combined organic extracts were washed with brine (1×30ml), dried (MgSO4) and evaporated to a dark oil (4.1g). The crude oil was purified by flash silica gel chromatography in Ethyl acetate/hexane (1:1) to yield (S)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-cyanomethylamino-2-phenylethane as a viscous oil 2.5g. 1H NMR (250MHz, CDCl3) δ 7.82 (1H, s, Ar), 7.79 (2H, s, ArH), 7.36 (5H, m, Ph), 4.67 (2H, s, OCH2Ar), 4.27 (1H, t, J=6.5Hz, PhCHN), 3.68 (1H, d, J=17Hz) and 3.31 (1H, d, J=17Hz, CH2CN). m/z (CI+) 403 (M+1, 100%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=[O:11])[CH3:10]>>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:9](=[O:11])[CH:10]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and commercial 3-acetylindole, 1-(1H-indol-3-yl)-3-phenylprop-2-en-1-one was obtained as orange coloured solid.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].O=[C:10]1[CH2:14][S:13][CH2:12][CH:11]1[C:15](OCC)=[O:16]>C(O)C>[N:3]1[C:10]2[CH2:14][S:13][CH2:12][C:11]=2[C:15]([OH:16])=[N:4][CH:2]=1
Reactant: CCOC(=O)C1CSCC1=O
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1ncnc2c1CSC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of formamidine HCl salt (3.70 g, 46.0 mmol) in ethanol (200 mL) was added NaOEt in ethanol (21% wt, 17.2 mL, 46.0 mmol). The mixture was stirred at room temperature for 1 hour. The ethyl 4-oxotetrahydrothiophene-3-carboxylate (8.0 g, 46.0 mmol) was added. The mixture was stirred at room temperature for 4 hours and then refluxed overnight. After cooling, the solvent was removed and the residue was washed with a small amount of water and CH2Cl2 to afford 5,7-dihydrothieno[3,4-d]pyrimidin-4-ol as light brown solid (2.5 g, 35%). 1H NMR (d6-DMSO, 400 MHz) δ 12.59 (s, 1H), 8.13 (s, 1H), 4.12 (s, 2H), 3.96 (s, 2H). MS (APCI+) [M+H]+ 155.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[C:17]3[CH3:19])=[N:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH3:20][C:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:11]1[N:18]2[C:14]([S:15][CH:16]=[C:17]2[CH3:19])=[N:13][CH:12]=1)[OH:10]
Reactant: Cc1csc2ncc(C(=O)CCc3ccccc3)n12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc2ncc(C(C)(O)CCc3ccccc3)n12

Procedure:
A solution of (2-Phenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-6) (0.40 g) in THF (6 mL) was treated with 3M ethereal methyl magnesium bromide (0.6 mL) and reacted for 18 hours. The suspension was treated with 5% NH4Cl solution and precipitated α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-7) was extracted into ethyl acetate. The extract was dried and evaporated to a viscous residue which deposited α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-7) (0.25 g) by ether trituration. Crystallization of the filter cake from ethyl acetate gave pure α,3-Dimethyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-7) (0.13 g), m.p. 131-133°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=102.5-105° C.). The reaction was monitored by tlc (Rf=0.25 in 50% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:14](=[O:20])[N:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:24]2[CH2:23][CH2:22][CH:21]([N:13]3[N:12]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:15]4([CH2:16][CH2:17][CH2:18][CH2:19]4)[C:14]3=[O:20])[CH2:26][CH2:25]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 4-(3,4-dimethoxyphenyl)-2-piperidin-4-yl-2,3-diazaspiro[4.4]non-3-en-1-one (compound B10) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclo hexane/EA=6:4) to yield the title compound.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCOc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Cyclohexyl{3-methyl-5-[2-(methylsulfanyl)ethoxy]-1-benzofuran-2-yl}methanone (0.73 g) synthesized in the above-mentioned (1) was dissolved in a tetrahydrofuran (10 mL) and methanol (5 mL), and sodium borohydride (90%, 0.18 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.67 g, 91%) as a pale-yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[S-:20][C:21]#[N:22].[K+]>CC(C)=O.CCOC(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][S:20][C:21]#[N:22])[C:6]([CH3:19])=[N:7]2)=[CH:12][CH:13]=1
Reactant: N#C[S-]
Reactant: COc1ccc(Cn2cc(C(=O)CBr)c(C)n2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(C(=O)CSC#N)c(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
According to Scheme 2, Step 3: To a solution of 2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone (9.28 mmol, 3.00 g) in acetone (19 mL) was added potassium thiocyanate (9.28 mmol, 0.90 g) and the reaction mixture was stirred overnight at room temperature. Then, the reaction mixture was diluted with EtOAc and the organic phase was washed with water. The organic phase was dried over MgSO4, was filtered and was concentrated. The crude residue was purified by flash chromatography over silica gel using cyclohexane/EtOAc (80:20 to 50:50) as eluent to yield 1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone (6.57 mmol, 1.98 g, 71%).
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32]S>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][S:10][CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: Fc1ccc(CS)c(F)c1
Product: CCOC(=O)C1=CCCCC1SCc1ccc(F)cc1F
Yield: 45 %

Procedure:
In the same manner as in Reference Example 1, ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (455 mg) and (2,4-difluorophenyl)-methanethiol (421 mg) were reacted to give ethyl 6-[(2,4-difluorobenzyl)sulfanyl]-1-cyclohexene-1-carboxylate (185 mg) as a colorless oil.