Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5])[CH3:3].C1COCC1.O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([O:11][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The active ester Z-Ala-Ala-OSu (1) was prepared according to a procedure described in Bodansky, M., Bodansky, A., The Practice of Peptide Synthesis 2nd Edition, Springer-Verlag. To a stirred solution of Z-Ala-Ala-OH (4.0 g, 13.6 mmol, obtained from Bachem) in 25 ml dry THF N-hydroxysuccinimide (1.56 g, 13.6 mmol) was added at 0° C. and the mixture was stirred for 10 minutes. A solution of dicyclohexylcarbodiimide (2.81 g, 13.6 mmol) in 3 ml dry THF was added. The mixture was stirred for 14 h, during which time it was allowed to warm to room temperature. The separated N,N′-dicyclohexylurea was removed by filtration and the solvent was evaporated in vacuo. The residue was twice recrystallized from isopropanol to give the active ester as a white solid (4.47 g, 84%) of m.p. 140° C.—TLC(MeOH/CHCl3, 1:50): Rf=0.5.—1H NMR (400 MHz, DMSO-d6): δ=1.20 (d, 3 H, J=7.0 Hz, CH3), 1.44 (d, 3 H, J=7.4 Hz, CH3), 2.79 (s, 4 H, 2×CH2), 4.04-4.10 (m, 1 H, CH), 4.63-4.69 (m, 1 H, CH), 4.96-5.04 (m, 2 H, CH2), 7.28-7.38 (m, 5 H, aryl-H), 7.45 (d, 1 H, J=7.8 Hz, NH), 8.58 (d, 1 H, J=7.0 Hz, NH).—MS (EI) m/z (%): 392 [M+H+], 414 [M+Na+], 430 [M+K+].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:27]([C:29]1[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=1)#[CH:28]>>[CH3:34][N:33]1[C:29]([C:27]#[C:28][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:30][N:31]=[CH:32]1
Reactant: O=C(NOCc1cccc(I)c1)c1ccccc1NCc1ccncc1
Reactant: C#Cc1cncn1C
Product: Cn1cncc1C#Cc1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1

Procedure:
Starring materials: N-(3-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see Example 361) and 5-ethynyl-1-methyl-1-H-imidazole (Aldrich).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].C([Mg]Cl)(C)C.CON(C)[C:23](=[O:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1.O.[Cl-].[Na+].O>[O:33]=[C:23]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Brc1ccncc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
4-Bromopyridine hydrochloride (1.1 g, 5.7 mmol) was treated with 5% Na2CO3 (aq, 35 mL) and the solution extracted with CH2Cl2 (3×15 mL). The extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to yield a oil. The oil was dried under high vacuum before the flask was flushed with nitrogen and then immediately dissolved in dry THF (15 mL). To this solution was added isopropylmagnesium chloride (2.6 M solution in ether, 2.2 mL, 5.7 mmol) dropwise under nitrogen. The resulting dark solution was stirred at room temperature for 1.5 h during which time a precipitate formed. Meanwhile, to a chilled (ice/acetone bath) suspension of tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (1.0 g, 4.6 mmol) in THF (10 mL) was added isopropylmagnesium chloride (2.6 M solution in ether, 1.8 mL, 4.7 mmol) dropwise. The resulting solution was stirred for 10 minutes before being added to the aryl Grignard initially generated. The mixture was stirred at room temperature overnight, diluted with water (25 mL) and brine (25 mL) and extracted with ethyl acetate (3×35 mL). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield a yellow residue. The material was purified by flash chromatography (Biotage SP4, 40 g cartridge, 1 gradient CV hexanes, 0-100% EtOAc in hexanes 10 CV, hold for 5 CV) to give tert-butyl [2-oxo-2-(pyridin-4-yl)ethyl]carbamate as a yellow oil (785 mg yield 52%). 1H-NMR (400 MHz, CDCl3): δ 1.47 (s, 9H), 4.65 (d, 2H, J 4.6 Hz), 7.71-7.74 (m, 2H), 8.83-8.86 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]12[C:20]([CH3:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][C:17](=NN)[CH:16]1[CH2:15][N:14]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:13]2)=[O:11].[I:37]I.C(OCC)(=O)C>O1CCCC1>[CH3:8][O:9][C:10]([C:12]12[C:20]([CH3:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH:18]=[C:17]([I:37])[CH:16]1[CH2:15][N:14]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:13]2)=[O:11]
Reactant: II
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2(C)c1ccccc1
Yield: 70.3 %

Procedure:
2.95 cm3 of triethylamine were added to a solution of 2.8 g (7 mmol) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-methyl-4-phenyloctahydroisoindole-3a-carboxylate in 80 cm3 of tetrahydrofuran and a solution of 3.6 g (14.1 mmol) of iodine in 40 cm3 of tetrahydrofuran was run in dropwise. After addition of ethyl acetate, the organic phases were washed with two times 50 cm3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 50 cm3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (85/15 by volume) mixture, 2.4 g (69%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained in the form of a yellow oil, the characteristic of which was as follows:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(N(CC)CC)C>CCOCC>[C:1]([O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:17])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 212 %

Procedure:
A solution of benzoyl chloride (32.5 g, Aldrich) in ether (200 ml) was added dropwise to a stirred solution of m-cresol (25.0 g, Aldrich) and triethylamine (27.2 g, Aldrich) in ether (500 ml). The reaction mixture was stirred at room temperature for 1 hour then filtered. The ethereal filtrate was washed with saturated NaHCO3 and water then dried over Na2SO4. The ether layer was separated, dried and concentrated in vacuo to give the desired product (104.0 g) as a white solid, mp 45-47C. 1H NMR consistent with the desired structure.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:12]=[CH:13][CH:14]=1.Cl.Cl[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35].C(OCC)(=O)C>CC(N(C)C)=O.O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCCC1CCCl
Reactant: COc1cccc(CCCCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(CCCCc2ccccc2OCCC2CCCN2C)c1
Yield: 47.5 %

Procedure:
1.48 g of potassium t-butoxide were added to a solution of 1.35 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7) in 20 ml of dimethylacetamide, whilst ice-cooling and stirring. 1.45 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochoride were then added to the solution, and the mixture was stirred at 55° C. for 2 hours. At the end of this time, the reaction mixture was cooled, 200 ml of ethyl acetate and 100 ml of water were added to the mixture, and the mixture was shaken. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.92 g (yield 48%) of the title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([O:30][CH3:31])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([O:30][CH3:31])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: COC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: COC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=480.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-methoxy-malonamic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.[C:16]([C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]2[CH2:31][CH2:30][CH2:29][C@@:25]2([CH3:32])[C:26](O)=[O:27])=[O:23])=[CH:20][CH:19]=1)#[N:17].S(Cl)(Cl)=O>>[C:16]([C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]2[CH2:31][CH2:30][CH2:29][C@@:25]2([CH3:32])[C:26]([N:1]2[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]2)=[O:27])=[O:23])=[CH:20][CH:19]=1)#[N:17]
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@]2(C)CCCN2C(=O)c2ccc(C#N)cc2)CC1

Procedure:
By reacting 1.67 g of t-butyl 4-piperidinyloxyacetate with 0.8 g of the acid chloride of 1-(p-cyanobenzoyl)-2-methyl-L-proline (obtained by treating the product of the previous step with thionyl chloride) there is obtained 0.89 g of t-butyl [[1-[1-(p-cyanobenzoyl)-2-methyl-L-prolyl]-4-piperidinyl]oxy]acetate. M.p. 180°-182° C. (ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCCCCC.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>C1COCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:32]([OH:35])[OH:33])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Into a solution of 19.6 g (60.7 mmol) of 3-bromo-9-phenylcarbazole, prepared in Step 1 of the Embodiment 2, in THF (100 mL) was added dropwise 66.8 mL (42.3 mmol) of an n-butyllithium hexane solution (1.58 mol/L) at −78° C. under nitrogen, which was followed by stirring for 3 hours at the same temperature. Thereafter, 13.5 mL (140 mmol) of trimethyl borate was added, and stirring was continued for 24 hours while gradually raising the reaction temperature to room temperature. 200 mL of 2.0 mol/L hydrochloric acid was added to the solution, and additional stirring was conducted for 1 hour at room temperature. After the solution was extracted with ethyl acetate, the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated. The resulting solid was recrystallized with a mixed solvent of chloroform and hexane, giving 10.2 g of 9-phenylcarbazole-3-ylboronic acid as white powder in 58% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:37]([NH:44][C@@H:45]([C:50](O)=[O:51])[CH2:46][CH2:47][S:48][CH3:49])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37](=[O:38])[NH:44][C@@H:45]([C:50]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:51])[CH2:46][CH2:47][S:48][CH3:49])([CH3:43])([CH3:41])[CH3:42]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Yield: 68 %

Procedure:
Following general amide formation method 1, 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined with BOC-D-Methionine (51 mg, 0.205 mmol, 1.0 eq) which gave ((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-3-methylsulfanyl-propylycarbamic acid tert-butyl ester (105 mg) in 68% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.56 (m, 14H) 1.63 (br. s., 2H) 1.68-1.82 (m, 3H) 1.82-1.99 (m, 4H) 1.99-2.18 (m, 10H) 2.48-2.68 (m, 5H) 3.18 (s, 7H) 3.73 (dd, J=10.36, 6.82 Hz, 1H) 4.51 (br. s., 1H) 4.69 (br. s., 3H) 4.77-4.89 (m, 2H) 5.28 (t, J=10.11 Hz, 1H) 6.51 (s, 1H) 7.80 (d, J=6.57 Hz, 1H) 8.36 (br. s., 1H) 8.42 (d, J=2.02 Hz, 1H) 8.59 (br. s., 1H) 8.80 (s, 1H). HRMS m/z, (M+H)+: 720.3682.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:27])[CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11]1(=[O:26])=[O:25])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33](=[O:35])[NH2:34])([CH3:31])([CH3:30])[CH3:29].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([NH:5][CH2:6][C:7](=[O:27])[CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:11]1(=[O:26])=[O:25])([CH3:4])([CH3:2])[CH3:3].[C:28]([O:32][C:33](=[O:35])[NH2:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)NCC(O)CCN1c2ccccc2N(c2ccccc2)S1(=O)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC(N)=O
Solvent: ClCCl
Product: CC(C)(C)NCC(=O)CCN1c2ccccc2N(c2ccccc2)S1(=O)=O
Yield: 147 %

Procedure:
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol-carbamic acid tert-butyl ester (15 mg, 0.031 mmol) and Dess Martin periodinane (20 mg, 0.046 mmol) were stirred in dichloromethane (5 mL) in a sealed vial at room temperature for 18 hr. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-50% ethyl acetate in hexane to afford 0.023 g of 1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-one-carbamic acid tert-butyl ester as a clear oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][C:19]([CH3:26])=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][C:19]([CH3:26])=[C:20]([CH2:22][C:23]([NH:34][CH2:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1sc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)nc1CC(=O)O
Reactant: NCC1CCOCC1
Product: Cc1sc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)nc1CC(=O)NCC1CCOCC1

Procedure:
Using the compound obtained in step 2 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]5[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=5Cl)(=[O:24])=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>C(Cl)Cl.CO.CO.C(Cl)Cl.[Pd]>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]5[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[CH:29]=5)(=[O:23])=[O:24])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:3][CH2:2]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(C)cc1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (300 mg, 0.49 mmol) in methylene chloride (125 mL) and methanol (125 mL) at 25° C. was treated with 10% Pd/C (1.0 g) and sodium acetate (134 mg, 1.22 mmol). The resulting mixture was hydrogenated in a Parr bomb at 50 psi for 24 h. At this time, the reaction was filtered through a pad of celite and was washed with an 8/2 methylene chloride/methanol solution (200 mL). The filtrate was concentrated in vacuo to afford a white solid. This solid was dissolved in a 5/95 methanol/methylene chloride solution. The organics were washed with water (1×25 mL). The aqueous layer was then back-extracted with chloroform (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (184 mg 65%) as a white solid; (ES)+-HRMS m/e calculated for C28H28FN7O4S (M+H)+ 578.1980, found 578.1987.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH2:11][CH:12]([OH:15])[CH2:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[CH2:11][CH:12]([O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH2:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CC=C(COCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(COCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a solution of 3-(benzyloxymethyl)cyclopent-3-enol (CAS 153186-83-5; Nucleosides, Nucleotides, and Nucleic Acids 26: 935-37, 2007) (5.75 g, 28.1 mmol) and imidazole (2.87 g, 42.2 mmol) in dry N,N-dimethylformamide (20 ml) at 0° C. was added tert-butyldimethylchlorosilane (5.09 g, 33.8 mmol). Stiffing was continued at 0° C. for 5 minutes, the cooling bath was removed and the mixture was stirred at 23° C. for 2 h. For the workup, the reaction mixture was poured into water, followed by extraction with TBME. The organic layer was washed with brine and dried over Na2SO4. Removal of the solvent at reduced pressure left a yellow oil, which was purified by flash chromatography (silica gel, 50 g, 0% to 15% EtOAc in heptane) to give the (3-(benzyloxymethyl)cyclopent-3-enyloxy)(tert-butyl)dimethylsilane (7.3 g, 81.4% yield) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([C:16](F)(F)F)[NH:6][C:7](=[O:15])[NH:8]2.COC1C(OC)=CC=C2C=1C(C(C)C)NC(=O)N2.C1(C2C3C(=CC=C(OC)C=3OC)NC(=O)N2)CCCCC1.COC1C(OC)=CC=C2C=1C(C)NC(=O)N2.COC1C(OC)=CC=C2C=1C(C(F)(F)F)=NC(=O)N2.COC1C(OC)=CC=C2C=1C(C(C)C)=NC(=O)N2.C1(C2C3C(=CC=C(OC)C=3OC)NC(=O)N=2)CCCCC1>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:16])=[N:6][C:7](=[O:15])[NH:8]2
Reactant: COc1ccc2c(c1OC)C(C(F)(F)F)NC(=O)N2
Agent: COc1ccc2[nH]c(=O)nc(C(C)C)c2c1OC
Agent: COc1ccc2[nH]c(=O)nc(C(F)(F)F)c2c1OC
Agent: COc1ccc2[nH]c(=O)nc(C3CCCCC3)c2c1OC
Product: COc1ccc2[nH]c(=O)nc(C)c2c1OC

Procedure:
When in the above procedure 3,4-dihydro-5,6-dimethoxy-4-trifluoromethyl-2(1H)quinazolinone, 3,4-dihydro-5,6-dimethoxy-4-isopropyl-2(1H)quinazolinone and 3,4-dihydro-4-cyclohexyl-5,6-dimethoxy-2(1H)quinazolinone are employed in place of 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quinazolinone the corresponding 5,6-dimethoxy-4-trifluoromethyl-2(1H)quinazolinone, 5,6-dimethoxy-4-isopropyl-2(1H)quinazolinone and 4-cyclohexyl-5,6-dimethoxy-2(1H)quinazolinone are obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[N:12]=[C:11]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:15][CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: Cc1cccc(CCO)n1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(CCOS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MsCl (6.7 mmol, 0.52 mL) was added to a solution of 6-methyl-2-pyridineethanol (6.7 mmol, 0.92 g) and triethyl amine (13.4 mmol, 1.88 mL) in toluene (6 mL) at 0° C. dropwise. The resulting mixture was stirred at 0° C. for 30 min. The precipitate generated from reaction was filtered off. The filtrate was concentrated in vacuo to give crude 2-(6-methylpyridin-2-yl)ethyl methanesulfonate which was used for next step without further purification. A mixture of above described 2-(6-methylpyridin-2-yl)ethyl methanesulfonate, PhOH (13.4 mmol, 1.26 g) and NaOH (13.4 mmol, 0.54 g) in isopropanol (20 mL) was refluxed at 90° C. for 3 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc which was washed with water. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography to give desired 2-methyl-6-(2-phenoxyethyl)pyridine as a colorless oil in 26% yield.