Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([CH3:17])[C:12]([CH:13]=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:18])[C:12]([CH2:13][OH:14])=[C:15]([CH3:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1CO
Yield: 96.3 %

Procedure:
Treat a solution of 4-Benzyloxy-2,6-dimethyl-benzaldehyde (6.4 g, 27 mmol) in Methanol (60 mL) with Sodium borohydride (0.82 g, 22 mmol). Stir the reaction for 1 hr at room temperature. Quench the reaction with a saturated solution of sodium bicarbonate in water and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 6.3 g (97%) of product. 1H NMR (d6-CDCl3) δ 7.31-7.43 (m, 5H), 6.65 (s, 2H), 5.01 (s, 2H), 4.66 (s, 2H), 2.38 (s, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[C:34](=[O:35])[C:33]2[N:25]([C:26]3[CH:27]4[CH2:36][CH:30]([C:31]=3[CH:32]=2)[CH2:29][CH2:28]4)[CH2:24][CH2:23]1)(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:62][O:61][CH2:60]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:22]2[C:34](=[O:35])[C:33]3[N:25]([C:26]4[CH:27]5[CH2:36][CH:30]([C:31]=4[CH:32]=3)[CH2:29][CH2:28]5)[CH2:24][CH2:23]2)=[CH:8][C:9]([F:21])=[CH:10][C:11]=1[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH:59]4[CH2:60][O:61][CH2:62]4)[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
A sealed tube was charged with 334h (300 mg, 0.6 mmol), 188e (254 mg, 0.6 mmol), Na2CO3 (129 mg, 1.2 mmol), PdCl2(dppf) (50 mg, 0.06 mmol) suspended in DMF (20 mL), and H2O (1 mL). The mixture was stirred at 80° C. for 5 hours. After reaction the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water (2×), dried over sodium sulfate and concentrated. The residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:5 water/CH3CN to give 334i as a brown solid (300 mg, 70%). MS: (M+H)+ 708.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>C1COCC1>[F:14][C:15]1[CH:20]=[C:19]([C:2](=[O:1])[CH2:6][CH2:5][CH2:4][NH:3][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In a round-bottomed flask was charged tert-butyl 2-oxopyrrolidine-1-carboxylate (2.2 g, 11.9 mmol) and THF (25 mL). The mixture was cooled down to −78° C. first, followed by slow addition of (3-fluorophenyl)magnesium bromide (17.8 mL, 17.8 mmol, 1.0 M solution in THF) over 15 minutes. The mixture was stirred for 3 hours, during which time the bath temperature rose from −78° C. to −10° C. The reaction was quenched by drop-wise addition of 1N HCl (2 mL) and warmed up to ambient temperature, followed by addition of EtOAc and water. After separating the organic layer, the aqueous layer was extracted with EtOAc three times. The combined organic layers was dried over Na2SO4 and concentrated to yield the product as a clear oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:41]=[C:40]3[C:36]([CH2:37][N:38]([C@@H:43]([CH:48]([CH3:50])[CH3:49])[C:44]([O:46][CH3:47])=[O:45])[C:39]3=[O:42])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[CH3:49][CH:48]([CH3:50])[C@H:43]([N:38]1[CH2:37][C:36]2[C:40](=[CH:41][C:33]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:8](=[O:10])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:32][CH:31]=3)=[CH:34][CH:35]=2)[C:39]1=[O:42])[C:44]([O:46][CH3:47])=[O:45]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(O)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Cc4ccccc4)cc3)cc2C1=O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 2-phenylacetic acid (150 mg, 1.102 mmol) in THF (5 mL) was added N-methylmorpholine (0.182 mL, 1.653 mmol) and cooled to −20 to −30° C. To this solution was added isobutyl chloroformate (0.145 mL, 1.102 mmol) and the reaction mixture was stirred at −20° C. for 30 min. To the reaction mixture, a solution of compound of example 6 (336 mg, 0.992 mmol) in THF (2.5 mL) was added and stirred at room temperature for 2-3 h. After completion of the reaction, EtOAc was added to the reaction mixture and washed with brine water. The organic extract was dried over anhydrous sodium sulfate and concentrated to obtain a crude material, which was purified by column chromatography (silicagel, 30% ethyl acetate in chloroform).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:1]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=2)=[O:19])[CH:14]=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(N)c2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C)cc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
Benzoyl chloride (7.5 g, 53 mmol) and 4-dimethylaminopyridine (1.0 g, 8.3 mmol) were added to a solution of 2-(2-amino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 27 mmol) in N,N-dimethylacetamide (100 mL) and the mixture was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (150 mL) and methanol (40 mL) and 1N aqueous solution of sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water (100 mL) was added and neutralized with 2N-hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 2:1) to obtain 6.4 g of the title compound (19 mmol, yield 70%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([OH:17])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C(C(Cl)=O)=CC=CC=1.[NH3:34]>CC(C)=O>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([NH2:34])=[O:17])([O-:3])=[O:2]
Reactant: N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)O
Agent: Cc1ccccc1C(=O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(N)=O

Procedure:
o-Toluoyl chlorides may be prepared by reacting 3,5-dinitro-4-chloro-o-toluic acid with phosphorus pentachloride. The resulting o-toluoyl chloride is then treated with ammonia in cold acetone to yield the corresponding 3,5-dinitro-4-chloro-o-toluamide which is converted to the corresponding nitrile by reaction with phosphorus pentoxide or preferably with POCl3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[CH:7][C:6]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:3])[CH3:2].[N+:37]([O-])([OH:39])=[O:38]>C(O)(=O)C>[N+:37]([C:8]1[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:7]=1)([O-:39])=[O:38]
Reactant: CCCCCCCCCCCCOc1ccc(OCCCCCCCCCCCC)c(NC(C)=O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c(OCCCCCCCCCCCC)cc1NC(C)=O
Temperature: 25 °C

Procedure:
The product of Stage 3 (22.8 g) is suspended in 250 ml of glacial acetic acid. 4.9 ml of nitric acid of density 1.39 are added dropwise with stirring at room temperature, the mixture becoming pasty. Following the addition of another 50 ml of glacial acetic acid, the mixture is stirred for a few hours and filtered under suction. The filtered residue is suspended twice with acetonitrile, filtered under suction and dried.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][C:22]=1[C:23]#[N:24]>>[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:29][C:26]4[CH:27]=[CH:28][C:21]([F:20])=[C:22]([CH:25]=4)[C:23]#[N:24])[CH2:17][CH2:18]3)[C:6]=2[CH:5]=1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl
Product: N#Cc1cc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)ccc1F

Procedure:
The title compound was prepared (392 mg, 41%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (655 mg, 2.4 mmol) and 2-fluoro-5-formylbenzonitrile (399 mg, 2.7 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.16 (m, 1H), 7.00 (s, 1H), 4.93 (d, 1H), 4.19 (m, 1H), 3.50 (s, 2H), 2.83 (d, 2H), 2.23 (dt, 2H), 2.10 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C19H18ClFN5S, 402.1; Observed: 402.2 (M++1).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5]C.C1(C#C)C=CC=CC=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#N)=[CH:18][CH:17]=1>C(C1C=CC(C#CCCCC)=CC=1)#CCCCC.C(#N)C1C=CC=CC=1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[C:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:18][CH:17]=1
Reactant: C#CCCCC
Reactant: N#Cc1ccc(Cl)cc1
Agent: CCCCC#Cc1ccc(C#CCCCC)cc1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCC#Cc1ccc(Cl)cc1
Reaction time: 20 h
Yield: 64.5 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-chlorobenzonitrile (0.275 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 1.29 mmol (65% yield) of 1-chloro-4-(1-hexynyl)benzene, 0.10 mmol 1,4-bis(1-hexynyl)benzene and no remaining 4-chlorobenzonitrile in the reaction mixture.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:44]>>[NH2:44][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C

Procedure:
A suspension of 1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (65 mg, 0.103 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to the title compound (64 mg). MS (ESI): 558.6 [M+1−56]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(I)ccc1OCc1ccccc1
Temperature: 120 °C

Procedure:
67.2 g (0.48 mol) of potassium carbonate are added to a solution of 100 g (0.40 mol) of 2-hydroxy-5-iodobenzaldehyde (Example 1A) in 1.5 l of dimethylformamide and, after a few minutes, 51 ml (0.44 mol) of benzyl chloride are added. The reaction mixture is stirred under reflux at 120° C. for 24 h. After stirring at RT for a further 24 h and the addition of 1.5 l of water, a solid crystallizes out. The precipitate is collected by suction filtration, washed twice with water and dried in vacuo. The solid is recrystallized from 230 ml of ethanol. 122.9 g (90% of theory) of product are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[Br:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:29]1([NH:34][C:35]2[N:43]=[CH:42][N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][N:39]3[C@H:44]2[CH:51]3[C@H:47]([O:48][C:49]([CH3:53])([CH3:52])[O:50]3)[C@@H:46]([CH2:54][CH:55]=O)[O:45]2)[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[Br:8]/[CH:9]=[CH:55]/[CH2:54][C@@H:46]1[C@@H:47]2[CH:51]([O:50][C:49]([CH3:53])([CH3:52])[O:48]2)[C@H:44]([N:39]2[CH:38]=[N:37][C:36]3[C:40]2=[N:41][CH:42]=[N:43][C:35]=3[NH:34][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[O:45]1
Reactant: CC1(C)OC2[C@H](n3cnc4c(NC5CCCC5)ncnc43)O[C@H](CC=O)[C@H]2O1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OC2[C@H](n3cnc4c(NC5CCCC5)ncnc43)O[C@H](C/C=C/Br)[C@H]2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of potassium-tert-butoxide (0.78 g, 6.93 mmol) in tetrahydrofuran (45 mL) was added (bromomethyl)triphenylphosphonium bromide (1.51 g, 3.27 mmol) in small portions at −78° C. The resulting mixture was stirred at −78° C. for 2 hours. 2-{(1R,2R,4R)-4-[6-(cyclopentylamino)purin-9-yl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}ethan-1-one, a compound of Formula (11) (0.89 g, 2.31 mmol) dissolved in THF (15 mL) was added slowly and the mixture stirred under an atmosphere of N2 at −78° C. for 3 hours, brought to room temperature slowly and stirred for 4 days. The reaction mixture was quenched with saturated NH4Cl aqueous solution (15 mL) and diluted with H2O (60 mL), and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×50 mL), dried over Na2SO4, and evaporated under reduced pressure, to provide {9-[4-((2E)-3-bromoprop-2-enyl)(2R,4R,5R)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]purin-6-yl}cyclopentylamine, a compound of formula (12), which was isolated by column chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:19][C:6]2=[C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:20])[C:3]1=[CH:21]O.Cl.[NH2:25]O>CCO.O>[CH3:1][C:2]1([CH3:23])[C:3]2[CH:21]=[N:25][O:20][C:4]=2[C:5]2=[C:9]([S:10][CH3:11])[S:8][C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[C:6]2[CH2:19]1
Reactant: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)C(=CO)C(C)(C)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=O)N2CCCC2)c2c1-c1oncc1C(C)(C)C2
Temperature: 25 °C

Procedure:
To a solution of 6,6-dimethyl-5-hydroxymethylene-3-methylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (173 mg, 0.49 mmol) in EtOH (4 mL) and water (0.7 mL) was added hydroxylamine hydrochloride (38 mg, 0.54 mmol). The solution was heated at reflux for 2 h then cooled to room temperature and the solvent evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer separated, dried (Na2SO4) and evaporated. The residue was triturated with hexane/Et2O and the resultant yellow solid (131 mg, 77%) collected by filtration. mp 114-116° C. C17H2ON20N2S2O2.0.1(H2O) requires: C, 58.29; H, 5.81; N, 8.00%. Found: C, 58.05; H, 5.59; N, 7.65%. 1H NMR (360 MHz, CDCl3) δ1.26 (6H, s), 1.94-1.98 (4H, m), 2.63 (3H, s), 2.90 (2H, s), 3.56-3.67 (4H, m), 8.20 (1H, s). MS (ES+) 349 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH2:8][O:7][C:6](=[O:9])[O:5][CH2:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][OH:28]>>[CH2:1]([C:3]([CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH2:8][O:7][C:6]([O:5][CH3:4])=[O:9])[CH2:27][OH:28])[CH3:2]
Reactant: C=CC(=O)OCC1(CC)COC(=O)OC1
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCC(CC)(CO)COC(=O)OC

Procedure:
Analogous to Example 1, the title compound was synthesized using 21.4 g of 5-ethyl-5-acryloyloxymethyl-2-oxo-1,3-dioxane, 96 g of methanol and 0.1 g of p-toluenesulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: COC(=O)/C=C/CC[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCC[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
Palladium-carbon (containing 50% water, 0.492 g) was added to a solution of tert-butyl (2S,5S)-2-(3,4-difluorophenyl)-5-[(E)-4-methoxycarbonyl-3-butenyl]pyrrolidine-1-carboxylate (1.7 g) in ethyl acetate (60 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. Palladium-carbon in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.7 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10]Br.[NH:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K]>CN(C)C=O>[C:23]([O:22][C:20]([N:12]([CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
A mixture of 4-bromo-3-bromomethylanisole (24 g, 86 mmol) and potassium di-tert-butyl iminodicarboxylate (24 g, 94 mmol) in dimethylformamide (200 mL) was stirred under argon at room temperature for 18 hr. The reaction was then concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried(MgSO4), and concentrated. The residue was recrystallized from hexane to give the title compound (15 g, 42%) as a white solid: 1H NMR (CDCl3) δ 7.40 (d, J=8.6 Hz, 1 H), 6.68 (m, 2 H), 4.81(s, 2 H), 3.74 (s, 3 H) 1.44 (s, 18 H).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].[ClH:22].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:28].[ClH:22].[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH3:3]
Reactant: CN(C)CCCCl
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCN(C)C)n1cnc(C(N)=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (20 mg), 3-(dimethylamino)propyl chloride hydrochloride (32.7 mg) and potassium carbonate (38 mg) in N,N-dimethylformamide (3 ml) was stirred overnight at 60° C. The mixture was evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, triethylamine, and methanol (20:1:4) and the product was treated with HCl in EtOAc to give a pale brown oil of 1-{(2S,3R)-2-hydroxy-5-[2-(3-dimethylaminopropoxy)phenyl]-3-pentyl}imidazole-4-carboxamide dihydrochloride (5) (21.2 mg).
Reaction SMILES: [N:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:4]2([NH2:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C2(N=[N+]=[N-])CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2(N)CCCCC2)c1
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 1-(1-azidocyclohexyl)-3-(methyloxy)benzene (D315) (2.78 g, 12.0 mmol, 1 equiv) in THF (20 ml) at room temperature was added LiAlH4 (1M in THF, 36 ml, 36 mmol, 3 equiv) and the resulting mixture was stirred at this temperature for 4 h. The mixture was then carefully quenched with a 1N aqueous NaOH solution (6 ml, 60 mmol, 1 equiv) then H2O. The mixture was filtered through a pad of celite then acidified with a 2N aqueous HCl solution (50 ml). The two layers were separated and the pH of the aqueous phase adjusted to 9 using a 2N aqueous NaOH solution. The aqueous phase was extracted three times with Et2O and the combined organic phase were dried over MgSO4 then concentrated in vacuo to give {1-[3-(methyloxy)phenyl]cyclohexyl}amine (F41) (1.55 g, 63%) as a clear oil which was used in the next step without further purification. [M+H]+=189.0, RT=1.90 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:25])([CH3:24])[C:18](=[O:23])[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:13]=2[CH:12]=1>>[CH:20]1([N:19]2[C:13]3[CH:12]=[C:11]([NH:10][C:7]([C:4]4[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=4)=[O:9])[N:16]=[CH:15][C:14]=3[C:17]([CH3:24])([CH3:25])[C:18]2=[O:23])[CH2:22][CH2:21]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: Cn1ccc(C(=O)O)n1
Product: Cn1ccc(C(=O)Nc2cc3c(cn2)C(C)(C)C(=O)N3C2CC2)n1

Procedure:
Prepared in analogy to example 26 from 1-methyl-1H-pyrazole-3-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as white crystals.