Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][CH2:9][C@H:10]([NH2:12])[CH3:11].SC1N(C)C=CN=1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C)[C@@H:27]([CH2:33][O:34]C(=O)C)[O:26][C@H:25]1[N:38]1[CH:46]=[N:45][C:44]2[C:39]1=[N:40][C:41]([Cl:48])=[N:42][C:43]=2Cl)(=O)C.N>>[Cl:48][C:41]1[N:42]=[C:43]([NH:12][C@H:10]([CH3:11])[CH2:9][S:8][C:4]2[N:3]([CH3:2])[CH:7]=[CH:6][N:5]=2)[C:44]2[N:45]=[CH:46][N:38]([C:39]=2[N:40]=1)[C@@H:25]1[O:26][C@H:27]([CH2:33][OH:34])[C@@H:28]([OH:29])[C@H:24]1[OH:23]
Reactant: C[C@@H](N)CSc1nccn1C
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: Cn1ccnc1S
Agent: N
Product: C[C@H](CSc1nccn1C)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 43 %

Procedure:
The title compound was prepared according to method A as described above in Example 1 by reacting (R)-1-(1-methyl-2-imidazolyl)thio-2-propylamine hydrochloride [prepared using the same method as described in Example 1 from 2-mercapto-1-methylimidazole (3.31 g, 29 mmol) and 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (5.08 g, 29 mmol) followed by acidic hydrolysis] (2.30 g, 11.1 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.46 g, 5.5 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N[(R)-1-(1-methyl-2-imidazolyl)thio-2-propyl]adenosine (1.1 g, 43%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.28 (3H, d, --CHCH3), 3.53-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'-and 3'-OH, 5.82 (1H, d, H-1'), 6.92 (1H, s, Ar--H) 7.20 (1H, s, Ar--H), 8.40 (1H, s, H-8), 8.55 (1H, s, N--H). HPLC retention time 19.3 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CCCOC(C)Cc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCOC(C)Cc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Then, 2.5 g (8 mM) of the thus-obtained (-)-4-acetoxy-4'-(2-propoxypropyl)biphenyl was dissolved in 30 ml of methanol, added with 20% NaOH aqueous solution, and sturred at room temperature for 2 hrs. After completion of the reaction, the reaction solution was added with 1N hydrochloric acid till pH 2-3, and then further added with 100 ml of ethyl acetate to subject extraction treatment. The resulting organic layer was water-washed and then concentrated under a reduced pressure to obtain 2.2 g of (-)-4-hydroxy-4'-(2-propoxypropyl)biphenyl (V-43) with 100% yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[O:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[OH-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25]>CCOC(C)=O>[Cl:29][C:28]([Cl:31])([Cl:30])[CH2:27][O:26][C:24](=[O:25])[NH:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:9]([O:10][CH2:11][CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(OCCO)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A solution of Intermediate 186a (1.0 g, 3.63 mmol) in EtOAc (20 mL) was treated with aqueous NaOH (1M, 6.53 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.529 mL, 3.85 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with a further 20 mL EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in DCM. The combined fractions were evaporated under reduced pressure and the product was triturated with DCM. The solid was filtered and washed with Diethyl ether to afford the title compound as a white solid (0.930 g, 58%). LCMS (Method 3): Rt 4.01 min, m/z 450 [M].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[O:26]>[Cl-].[Na+].O.O1CCCC1.CCCCCC>[Cl:13][C:14]1[C:19]([CH:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[OH:26])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccccn1
Reactant: O=Cc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccs1)c1cccnc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
Under an atmosphere of argon, 1.6 M hexane (30 ml) solution of n-butyl lithium was added dropwise to a tetrahydrofuran (200 ml) solution of diisopropylamine (5.52 g, 54.7 mmol) which was cooled at -78° C., and the mixture was stirred for 30 minutes 2-Chloropyridine (5.71 g, 50.3 mmol) was added dropwise to the reaction solution, followed by 90 minutes of stirring. 2-Thiophenecarbaldehyde (6.01 g, 53.7 mmol) was added dropwise to the reaction solution, followed by 30 minutes of stirring. The reaction solution was mixed with brine and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to give α-(2-chloropyridin-3-yl)-2-thiophenmethanol (6.66 g, 27.5 mmol, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=2)[O:17][CH2:16]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=2)[O:17][CH2:16]1)=[O:8]
Reactant: Cc1ccc2c(c1)OCC(N)C2=O
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)ccc2C1=O
Temperature: 0 °C

Procedure:
17.5 g (85 mmol) of 5-chloro-2-methoxybenzoyl chloride were added to a solution of 18.2 g (85 mmol) of 3-amino-7-methyl-4-chromanone hydrochloride (Hebd. Seances Acad. Sci. Ser. C. 279, 281-284) in 90 ml of pyridine at room temperature. After the mixture had been stirred for 2 hours (TLC control: silica gel plate using petroleum ether/ethyl acetate/toluene 2:2:1), it was introduced into ice/water. The precipitate was filtered off with suction, washed several times with water and dried. The 3-(5-chloro-2-methoxybenzamido)-7-methyl-4-chromanone had a melting point of 177°-178° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20]>C(#N)C.C(OCC)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)N1CCN(CCCO)CC1
Yield: 79.4 %

Procedure:
1-Acetylpiperazine (15.0 g, 117 mmol) was dissolved in acetonitrile (200 ml) and potassium carbonate (40.4 g, 293 mmol) was added followed by 3-bromo-1-propanol (10.6 ml, 117 mmol). The mixture was heated at reflux for 2.5 hours, cooled, filtered and concentrated under reduced pressure. The resulting viscous oil was cooled in ice for 3 hours and the crystalline product that formed was suspended in diethyl ether and filtered off. The hydroscopic solid was dried under vacuum (P2O5) overnight to give 3-(4-acetylpiperazin-1-yl)propan-1-ol (17.3 g, 90%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][CH2:15]O)[CH:3]=1.P(Br)(Br)[Br:18].O>C1(C)C=CC=CC=1>[Br:18][CH2:15][CH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: OCCc1cc(Cl)ccc1-c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2)c(CCBr)c1
Reaction time: 20 h
Yield: 119.4 %

Procedure:
To a solution, maintained at 5° C., of 710 mg (3.05 mmol) of 2-(4-chlorobiphenyl-2-yl)ethanol, prepared in Example 51, in 10 ml of toluene are added 97 μl (1.02 mmol) of PBr3, and the reaction medium is allowed to return to room temperature. After stirring for 20 hours, the reaction medium is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and then concentrated under vacuum to give a yellow liquid, which is purified by flash chromatography on a column of silica, in dichloromethane. 360 mg of a pale yellow oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=3[CH:9]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl.O>[CH:21]1([NH:24][C:17]([C:16]2[C:10]3[CH:9]=[C:8]([C:6]4[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=4)[S:12][C:11]=3[CH:13]=[CH:14][CH:15]=2)=[O:19])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: NC1CC1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
A suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (5.00 g, 15.4 mmol) in dichloromethane (100 mL) is treated at room temperature with cyclopropylamine (1.20 mL, 17.3 mmol) in the presence of N,N-diisopropylethylamine (3.00 mL, 17.2 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.34 g, 17.4 mmol), and 1-hydroxybenzotriazole (2.33 g, 17.2 mmol) for 20 hours. Water (20 mL) is then added, and after stirring for 20 minutes, the mixture is filtered, and dried. The obtained solid is suspended in dichloromethane (50 mL), stirred for 2 hours, filtered, and dried to provide the title compound (5.60 g, 99%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:31][C:32]4[C:38]([CH3:39])=[CH:37][C:36]([C:40]#[N:41])=[CH:35][C:33]=4[N:34]=3)=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[C:40]([C:36]1[CH:37]=[C:38]([CH3:39])[C:32]2[O:31][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:23]([NH:22][CH2:21][CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[O:42])=[CH:29][CH:28]=3)=[N:34][C:33]=2[CH:35]=1)#[N:41]
Reactant: Cc1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)CC4)cc3)oc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Reaction time: 1 h
Yield: 124.9 %

Procedure:
To a solution of trifluoroacetic acid (2 ml) in dichloromethane (2 ml) was added 4 tert-butyl-4-({[4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate (68 mg). The mixture was stirred for 1 h, and then concentrated in vacuo to provide 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (67 mg. 99%). Half of this sample was added to potassium carbonate (19 mg) in ethanol. 4-Trifluoromethylbenzyl bromide (17 mg) was added and the mixture was heated to 70° C. for 4 h. The sample was cooled to room temperature, concentrated in vacuo, and was purified via preparative thin-layer chromatography (Rf=0.58 in 1:1 hexanes-ethyl acetate) to provide the title compound (31 mg, 84%). Mass spectrum (ESI) 533.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.57 (d, J=7.6 Hz, 2H), 7.48 (s, 1H), 7.44 (d, J=7.6 Hz, 2H), 6.23 (t, J=6.4 Hz, 1H), 3.55 (s, 2H), 3.42 (t, J=6.2 Hz, 2H), 2.99 (m, 2H), 2.65 (s, 6H), 2.03 (m, 2H), 1.76, m (2H), 1.42 (m, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][N:33]=[C:32]2[O:39][CH2:40][CH:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1>ClC(Cl)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:47][CH:44]3[CH2:45][CH2:46][CH:41]([CH2:40][O:39][C:32]4[C:31]5[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=5)[N:35]=[CH:34][N:33]=4)[CH2:42][CH2:43]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncnc(OCC3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2ncnc(OCC3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 2 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxin-6-carbaldehyde (0.045 g, 0.27 mmol) and then sodium triacetoxyborohydride (0.08 g, 0.377 mmol) were added to a solution of 4-(6-methoxyquinazolin-4-yloxymethyl)-cyclohexylamine (0.07 g, 0.25 mmol) in dichloroethane (1 ml). The reaction mixture was stirred for 2 hours and then filtered over Hydromatrix (wetted with NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 and then dichloromethane/MeOH 6/1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:18][CH2:19][OH:20])=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1cccc(Br)c1
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To detach the protecting group, 70 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were taken up in 1.5 ml of methanol and, after addition of 0.15 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. The reaction solution was concentrated by rotary evaporation and the residue purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and freed of the solvent under reduced pressure. The residue was dissolved in acetonitrile and lyophilized. This gave the product (38.6 mg) with a molecular weight of 467.4 g/mol (C20H23BrN2O4S); MS (ESI): m/e=468 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CN[C@@H]1CCCC[C@H]1NC.[CH3:41][OH:42]>[Cu]I>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CO
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Product: COc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cn1
Temperature: 150 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.060 g, 0.14 mmol) in 2 mL of methanol under an atmosphere of nitrogen was added trans-N,N′-dimethylcyclohexane-1,2-diamine (6.0 mg, 0.042 mmol) and copper(I) iodide (6.0 mg, 0.033 mmol). The mixture was heated at 150° C. for 15 h in a sealed pressure vessel, cooled to rt, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 417.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.41 (s, 1H), 8.68 (s, 1H), 8.60-8.54 (m, 1H), 8.36-8.28 (m, 2H), 8.09 (s, 1H), 8.05 (s, 1H), 7.40-7.38 (m, 1H), 6.66 (d, J=8.3 Hz, 1H), 4.58 (br s, 1 H), 4.47 (s, 2H), 4.09 (br s, 1H), 3.90 (s, 3H), 2.61 (br s, 1H), 2.30-2.27 (m, 1H), 2.05-1.92 (m, 4H), 1.40-1.32 (m, 2H).
Reaction SMILES: CCCC[Si](CC)CC.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18]=[CH:19][C:20]1C=C[C:23](C=C)=[CH:22][CH:21]=1.[SiH4].COC1C=CC=CC=1C(N1CCC[C@H]1CO)=O>C(Cl)Cl>[CH:16]1[C:17]2[C:12](=[CH:11][C:10]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=1
Reactant: C=Cc1ccccc1
Reactant: C=Cc1ccc(C=C)cc1
Agent: CCCC[Si](CC)CC
Agent: COc1ccccc1C(=O)N1CCC[C@H]1CO
Agent: [SiH4]
Solvent: ClCCl
Product: c1ccc2cc3ccccc3cc2c1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
We were able to successfully load representative primary alcohols to silane resin VIIIa and cleave the resins to afford high yields of alcohol products (Scheme 13). In a typical experiment, 200 mg PS-DES-silane resin was combined with a DCM solution of 1.7 mg of Rh2 (pfb)4 in 10 mL round bottle flask under argon. Then 66 mg of (s)-(-)-1-(2-methoxybenzoyl)-2-pyrrolidinemethanol was added at room temperature and the reaction was monitored by IR. After 3 hrs, the reaction was complete (as evidenced by the disappearance of the Si-H stretch at 2100 cm-1), the reaction mixture was filtered, and washed with 3×DCM, 2×toluene, 2×THF/H2O (1:1), 3×THF. The product was dried under vacuum in a dessicator. This product was then treated with AcOH/THF/H2O (6:6:1) for 12 hrs and the filtrate was concentrated by speedvac (rt, 80 mins) to obtain alcohol with 99.3% yield (GC, anthracene as internal standard).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:16])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C1COCC1>CO>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:15]([NH:14][C:11]2[O:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)=[O:16])[N:18]=1
Reactant: COC(=O)c1cccc2nc(NC(=O)c3cc4ccccc4cn3)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccc(C(=O)O)c2o1)c1cc2ccccc2cn1

Procedure:
2-[(Isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid was synthesized according to General Procedure B using 417 mg (1.2 mmol) 2-[(isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid methyl ester, 2.4 mL of 2 N aq. LiOH, 12 mL of THF and 3 mL of methanol at 40° C. for 4 h. 141 mg (0.423 mmol, 35%) of the product was obtained. LCMS: 334 (M+1)+.
Reaction SMILES: [C:1]([CH2:5][CH2:6][S:7][C:8]1[S:12][CH:11]=[N:10][C:9]=1[C:13]([O:15]C(C)(C)C)=[O:14])([O:3][CH3:4])=[O:2]>FC(F)(F)C(O)=O>[C:1]([CH2:5][CH2:6][S:7][C:8]1[S:12][CH:11]=[N:10][C:9]=1[C:13]([OH:15])=[O:14])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCSc1scnc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSc1scnc1C(=O)O

Procedure:
7.8 g of tert.-butyl 5-(2-carbomethoxyethylthio)-1,3-thiazol-4-ylcarboxylate are stirred in a mixture of 100 ml of trifluoroacetic acid and 100 ml of methylene ohloride at room temperature for 30 min. The solvent is removed in vacuo, and the residue is extracted by stirring with 100 ml of ether/petroleum ether (50°-70° C.) 1/1. After filtration and drying, 6.2 g of melting point 112°-116° C. are obtained, melting point 120°-121° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]([NH:67][CH3:68])=[O:66])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:59][CH2:60][N:61]([CH2:64][C:65]([NH:67][CH3:68])=[O:66])[CH2:62][CH2:63]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)-N-methylacetamide. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.86 (m, 11H) 1.95 (d, J=4.29 Hz, 2H) 2.15 (t, J=10.61 Hz, 2H) 2.62 (s, 3H) 2.81 (d, J=11.37 Hz, 2H) 2.90 (s, 2H) 3.33 (s, 3H) 3.94 (s, 3H) 4.05 (t, J=14.02 Hz, 2H) 4.77 (t, J=8.46 Hz, 1H) 7.43-7.53 (m, 2H) 7.57-7.69 (m, 1H) 7.97 (s, 1H) 8.14 (d, J=7.58 Hz, 1H) 8.20-8.35 (m, 2H) [M+H] calc'd for C29H38F2N8O4, 601. found 601.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:4][N:3]1[CH2:15][CH2:16][CH:17]=O.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:26]=[CH:25][C:24]([C@:27]23[CH2:32][C@H:31]2[CH2:30][NH:29][CH2:28]3)=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO.CC(O)=O>[N:10]1[CH:11]=[CH:12][N:13]=[CH:14][C:9]=1[C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[N:3]([CH2:15][CH2:16][CH2:17][N:29]2[CH2:30][C@H:31]3[C@:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:34])[F:33])=[CH:26][CH:25]=4)([CH2:32]3)[CH2:28]2)[CH:4]=1
Reactant: O=CCCn1cc(-c2cnccn2)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cnccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of 3-(2,4-dioxo-5-pyrazin-2-yl-3,4-dihydro-2H-pyrimidin-1-yl)-propionaldehyde (Prep127, 0.38 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 86 mg, 0.38 mmol), and AcOH (26 μl) in dichloroethane-MeOH (10-0.5, 4 ml) was cooled to 0° C. NaBH(AcO)3 (84 mg, 0.40 mmol) was added portionwise. The mixture was stirred at 0° C. for further one hour and then basified with 1N NaOH. The product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in the presence of PS-isocyanate. The mixture was filtered and the solvent evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) to give 78 mg of the title compound (45% yield).