Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[C:13]([OH:18])([CH2:16][CH3:17])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)[O:18][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CSc1ccc(OC(=O)Cl)cc1
Reactant: CCC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(=O)Oc1ccc(SC)cc1
Reaction time: 2 h

Procedure:
One hundred ml of dichloromethane and 20.27 g (0.1 mol) of p-methylthiophenyl chloroformate prepared in the same manner as in Example 1 were placed in a flask, and 50 ml of a dichloromethane solution containing 8.15 g (0.1 mol) of tertamyl alcohol and 8.70 g (0.11 mol) of pyridine was dropped thereto at room temperature. The resulting mixture was then stirred for two hours. The reaction solution was washed with water to remove pyridine hydrochlorate, and the organic layer was concentrated under reduced pressure. Finally excessive pyridine was removed in vacuum whereupon 5.09 g of the desired product, tert-amyl p-methylthiophenyl carbonate was obtained as an oily material (yield 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromophenol (27.4 g, 158 mmol) in CH2Cl2 was added chloromethyl methyl ether (18 mL, 237 mmol). The reaction mixture was cooled to 0° C. and diisopropylethylamine (55 mL, 316 mmol) was added and the cold bath was removed. The reaction mixture was stirred for 3 hours at ambient temperature and then poured into 10% aqueous HCl. The layers were separated and the aqueous phase was extracted 4 times with CH2Cl2. The combined organic layers were washed once each with saturated aqueous NaHCO3, 15% aqueous NaOH, and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 3-methyloxymethoxy-bromobenzene as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:9][C:3]1([C:7]#[N:8])[C:2](=[O:1])[CH2:6][S:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: N#CC1CSCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC1(C#N)CSCC1=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of 4-oxotetrahydrothiophene-3-carbonitrile (0.50 g, 3.9 mmol) in anhydrous acetone (7.8 mL) was added potassium carbonate (1.63 g, 11.8 mmol), followed by iodomethane (0.56 g, 3.9 mmol). The resulting mixture was stirred at 35° C. for 1 hour. The mixture was cooled to ambient temperature, filtered, and carefully concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-])=O.[NH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16]([O-])([O-])=[O:17].[K+].[K+]>>[C:16]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [K+]
Product: O=C(O)CNC(=O)c1ccccc1
Reaction time: 18 h

Procedure:
To a nitrophenol resin (TG-2a) (10 mg, 3.5 μmol) was added 0.1 M glycin in 0.1 M K2CO3. The reaction was stirred for 18 hours. The reaction mixture was filtered and washed with H2O. The washer was combined and acidified with acetic acid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added cyclohexanecarbonyl chloride (126 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 69%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[CH3:26][O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: CI
Reactant: COc1ccccc1C1CCC(CO)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CCC(c2ccccc2OC)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxymethyl-5-(2-methoxyphenyl)-N-(carbobenzyloxy)-tetrahydropyrrole (2.49 g, 7.30 mmol) in DMF (20 mL) at 0-40° C. was added methyl iodide (4.55 mL, 73 mmol) and NaH (60% oil dispersion, 1.75 g, 43.8 mmol) and the resulting suspension was stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O at 0° C., ether was added, and the aqueous layer was extracted with ether (×4), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc-95% hexanes) to provide the title compound as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OMe), 3.38 (3H, s, OMe).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:9]([OH:10])[CH2:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:9]([O:10][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)[C@@H]1[C@H](O)CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 77C (3.3 g, 12.7 mmol) in DCM (50 mL) was added DIPEA (6.63 mL, 38.1 mmol), tert-butyldimethylsilyl chloride (3.83 g, 25.4 mmol, 2.0 equiv) and DMAP (310 mg, 5.24 mmol, 0.2 equiv). The resulting mixture was stirred at rt overnight. TLC showed no completion and therefore another 2.2 mL of DIPEA and 1.91 g of tert-butyldimethylsilyl chloride were added and stirred at rt for 3 days. The mixture was concentrated and the residue was diluted with EtOAc (100 mL), washed with 0.5 N HCl (2×30 mL), brine (2×30 mL), dried (MgSO4) and evaporated to give the crude product as a light pink oil. Purification of the crude product by flash chromatography (5-10% EtOAc/hexane) gave the desired product 77D (3.8 g, 81%): Rf (10% EtOAc/hexane) 0.25; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.3 min (100%); MS (ES) m/z 374 [M+1]+.
Reaction SMILES: S(Cl)(Cl)(=O)=O.Cl[CH2:7][Cl:8].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:23][N:22]4[CH2:31][CH2:32]C[C:21]=34)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:23][N:22]4[CH2:31][CH2:32][CH:7]([Cl:8])[C:21]=34)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: ClCCl
Reactant: Brc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: ClC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Reaction time: 18 h

Procedure:
A solution of 1 M sulfuryl chloride in dichloromethane (20 mL, 20 mmol) is added to a solution of 7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (2.2 g, 5.62 mmol) in dry pyridine (50 mL). The mixture is stirred for 18 h and concentrated in vacuo. The residue is partitioned between chloroform and saturated sodium chloride. The organic layer is dried (sodium sulfate), filtered, concentrated in vacuo, and the residue chromatographed on SiO2 (dichloromethane to 20% methanol in dichloromethane) to yield the title compound as a red solid, 1.8 g (75%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([F:38])[CH:32]=2)[C@@H:29]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[CH2:28][C@@:27]([CH2:47][C:48](O)=[O:49])([CH3:46])[C:26]1=[O:51])[CH:22]1[CH2:24][CH2:23]1)(=[O:19])=[O:18])([CH3:16])([CH3:15])[CH3:14].[NH2:52][C:53]1[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[C:55]([O:63][CH3:64])[CH:54]=1.Cl>N1C=CC=CC=1.CCOCC>[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([F:38])[CH:32]=2)[C@@H:29]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[CH2:28][C@@:27]([CH2:47][C:48]([NH:52][C:53]2[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[C:55]([O:63][CH3:64])[CH:54]=2)=[O:49])([CH3:46])[C:26]1=[O:51])[CH:22]1[CH2:23][CH2:24]1)(=[O:19])=[O:18])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)S(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)c(F)c1
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)c1ccc(NC(=O)C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)c(F)c3)N([C@H](CS(=O)(=O)C(C)(C)C)C3CC3)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 76 g, 398 mmol) was added to a mixture of 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (79.4 g, 133 mmol, Example 4, Step J) and methyl 4-amino-2-methoxybenzoate (26.4 g, 146 mmol) in pyridine (332 mL) at 3° C. The mixture was allowed to warm to room temperature and was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and added to an ice-cold solution of 1 M hydrochloric acid (1 L). Ether (1 L) was added and the layers were agitated and then separated. The organic layer was washed with 1 M hydrochloric acid (6×500 mL), saturated aqueous sodium bicarbonate (500 mL), brine (500 mL), dried over magnesium sulfate, filtered and concentrated under a vacuum to provide an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1Br.C(=O)([O-])[O-].[Na+].[Na+].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)cc1-c1cccs1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.21 mmol) was added to a solution of 4-methoxy-3-bromobenzaldehyde (1.5 g, 6.98 mmol) in toluene (15 mL) and ethanol (15 mL), followed by a 2 M aqueous solution of sodium carbonate (14 mL, 28 mmol). To this mixture was added thiophene-2-boronic acid (0.98 g, 7.68 mmol), and the mixture was heated to reflux. After 3 hours, the reaction was partitioned between water (100 mL) and ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL), dried with magnesium sulfate and concentrated. Chromatography (silica, 20% ethyl acetate/hexanes) afforded 1.3 g (87%) of 4-methoxy-3-thiophen-2-yl-benzaldehyde as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.ClCCl>O>[CH3:14][O:13][CH2:12][CH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=1
Reactant: C1COCCN1
Reactant: COCCc1nc(Cl)c2nc[nH]c2n1
Solvent: O
Solvent: ClCCl
Product: COCCc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 75 %

Procedure:
6-Chloro-2-(2-methoxy-ethyl)-9H-purine (0.5 g, 2.4 mmol, synthesized by following the procedure reported by Crespo and al.(Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21, p. 4024) was heated in morpholine (1 mL, 5 eq) at 150° C. for 15 minutes. Reaction mixture was cooled to room temperature and distributed between dichloromethane and water. Organic layer was washed 2 times with water, then with brine, dried over MgSO4 and 2-(2-methoxy-ethyl)6-morpholin-4-yl-9H-purine (0.46 g, 75%) was isolated by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])=[N:46][CH:47]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH3:57])[CH2:54][CH2:55]6)=[O:49])=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)c2ccc(Br)cn2)CC1
Agent: COC(=O)c1ccc(Br)cc1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cn2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (5-bromo-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone (61 mg) obtained in the same manner as Step A in Example 1-D-79 instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, to obtain a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-ethyl-piperazin-1-yl)-methanone, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-95) as a milky white powder (52 mg, 54%).
Reaction SMILES: [F:1][C:2]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH:7]([OH:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].N1C=CC=CC=1.C(OC(=O)C)(=O)C.[CH:30](=[N:36]/O)/[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[F:1][C:2]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH:7]([O:8]/[N:36]=[CH:30]\[C:31]2[O:35][CH:34]=[CH:33][CH:32]=2)[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10]
Reactant: CC(C)OC(=O)C1(F)C(=O)NC(=O)NC1O
Reactant: O/N=C\c1ccco1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)OC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
In 50 ml of acetone was dissolved 20.0 g (85.4 mmol) of isopropyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, and 8.78 g (111.0 mmol) of pyridine and 8.65 g (93.9 mmol) of acetic anhydride were added to the solution, followed by stirring under ice-cooling for 3 hours and subsequently at room temperature for 16 hours. The solvent was disttiled off under reduced pressure, and the acetylated compound, which precipitates after the addition of water, was recovered by filtration, washed with water and dried. One-half its amount and 5.70 g (51.2 mmol) of (Z)-furfuraldoxime were dissolved in 30 ml of pyridineacetone (pyridine:acetone=2.1), and the solution was stirred at 60° C. for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane-ethyl acetate changing gradually the mixing ratio from (9:1) to (1:2) to yield 5.5 g of 5-fluoro-6-[(Z)-furfurylideneaminooxy]-5-isopropyloxycarbonyl-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine. m.p. 131°-134° C.
Reaction SMILES: [F:1][C:2]1[N:6](COCC[Si](C)(C)C)[CH:5]=[N:4][C:3]=1[CH2:15][N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>O1CCCC1>[F:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:15][N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: C[Si](C)(C)CCOCn1cnc(CN2CCCc3ccccc32)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Fc1[nH]cnc1CN1CCCc2ccccc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
To a stirred solution of 1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-ylmethyl]-1,2,3,4-tetrahydroquinoline (103 mg) at room temperature in tetrahydrofuran (THF) (5 ml) under an argon atmosphere was added tetra-n-butylammonium fluoride (TBAF) (1.1 ml; 1 M solution in THF). The mixture was heated to 60° C. and stirring at that temperature was continued for 20 minutes, then the mixture was adsorbed directly on silica gel. The crude product was isolated by column chromatography (silica gel; gradient: cyclohexane→ethyl acetate) to give 1-(5-fluoro-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline (32 mg) as light yellow solid. (MS (ISP): 232.1 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[F:26][C:27]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=1[CH2:29][Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:27]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=1[CH2:29][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Fc1ccc(F)c(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(Cc3cc(F)ccc3F)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Examples 127–146, the title compound was prepared (18 mg, 53%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), 2,5-difluoro-benzylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 340 (base, M+H).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1.[OH2:13].[O:14]1[CH2:18]C[CH2:16][CH2:15]1>>[CH2:15]([O:14][C:18]([C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1)=[O:13])[CH3:16]
Reactant: C1CCOC1
Reactant: O
Reactant: Brc1cscc1Br
Agent: CC(C)[Mg]Cl
Product: CCOC(=O)c1cscc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
Isopropylmagnesium chloride (263 mL of a 2.0 M solution in tetrahydrofuran, 0.527 mol) was added via cannula over 35 min to a solution of 3,4-dibromo-thiophene (102 g, 0.421 mol) in tetrahydrofuran (600 mL) at 0° C. The mixture was allowed to warm to 25° C. and was stirred at that temperature for 18 h. Water (25 mL) was added, and the mixture was stirred at 25° C. for 15 min, and then was concentrated in vacuo to ˜200 mL volume. The concentrate was partitioned between 1.0 M aqueous hydrochloric acid solution (400 mL) and ethyl acetate (2×350 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo to afford the crude product, 4-bromo-thiophene-3-carboxylic acid ethyl ester (91.9 g, 0.391 mol, 93%), as a yellow/brown oil. 1H NMR (400 MHz, CDCl3) δ: 1.40 (3H, t, J=7.5 Hz), 4.36 (2H, q, J=7.3 Hz), 7.31 (1H, d, J=3.9 Hz), 8.10 (1H, d, J=3.0 Hz).
Reaction SMILES: C([O:4][C@@H:5]([CH3:42])[C@@H:6]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([CH2:29][OH:30])[C:25]([O:27]C)=[O:26])=[O:22])=[O:15])=[O:8])(=O)C.CO.[NH3:45]>CO>[CH2:35]([O:34][C:32](=[O:33])[NH:31][C@H:6]([C@@H:5]([OH:4])[CH3:42])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21](=[O:22])[NH:23][C@@H:24]([CH2:29][OH:30])[C:25]([O:27][NH2:45])=[O:26])=[O:15])=[O:8])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)=O
Reactant: N
Solvent: CO
Product: C[C@H](O)[C@@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)ON
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of compound 6 (250 g, 0.42 mmol) in CH3OH (2 mL) was added MeOH—NH3 (10 mL) and was stirred at RT for 16 h. The volatiles were evaporated under reduced pressure to afford compound 7 (190 mg, 84%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]1[I:18])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:21])=O.C(N)C1C=CC2OCOC=2C=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C.C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH2:10][Cl:21])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]1[I:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(I)nc(-c2ccccc2)c1CO
Reactant: O=S(Cl)Cl
Agent: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCn1c(I)nc(-c2ccccc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Butyl-5-hydroxymethyl-2-iodo-4-phenylimidazole (1.96 g, 6.1 mmol) is dissolved in 20 ml dichloromethane and cooled to 0° C. To the solution is added 5 equivalents of thionyl chloride and the resulting solution is stirred at room temperature for 2 h. The reaction mixture is evaporated at reduced pressure and 20 ml of toluene is added to the residue and evaporated to remove any residual thionyl chloride. The crude product is dissolved in 20 ml of anhydrous acetonitrile and added to an ice-cooled solution of piperonyl amine (2.0 eq.) in acetonitrile (10 mL) containing potassium carbonate (2 eq.). The resulting mixture is stirred at room temperature for 4 h, diluted with 100 ml of ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated at reduced pressure. The residue is purified by silica gel chromatography (hexanes/ethyl acetate, from 2:1 to 1:1) to give 2.28 g of 1-butyl-5-chloromethyl-2-iodo-4-phenylimidazole. MS (+VE) m/z 490 (M+1).