Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].CO[C:16](OC)([CH3:18])[CH3:17]>CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:10][C@@:2]12[CH2:1][C@@H:6]([O:13][C:11]1=[O:12])[C@H:5]1[C@H:4]([O:9][C:16]([CH3:18])([CH3:17])[O:8]1)[CH2:3]2
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2[C@H]3C[C@@](O)(C[C@H]2O1)C(=O)O3
Yield: 86.2 %

Procedure:
A solution of quinic acid (10.0 g, 52.0 mmol), para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) and 2,2-dimethoxypropane (20 mL, 162.9 mmol) in acetone (150 mL) was refluxed for 4 hours. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated. The concentrate was stored at 0° C. for several hours to afford 9.6 g (86%) of the desired product as white crystals.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12].Cl.O>CO>[CH3:1][C:2]1([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]2[C:6](=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[O:12]1
Reactant: CC(=CCc1ccc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCCC1(C)CCc2ccc(O)cc2O1
Yield: 70 %

Procedure:
A solution of 4-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,3-benzenediol (870 mg; 2.24 mmole) and conc. hydrochloric acid (2.0 ml) in methanol (15 ml) was heated under reflux for 4 hours, then the reaction solution was poured into 70 ml of water and was extracted twice with isopropyl ether (50 ml). The extract was washed with 100 ml of water (twice) and 100 ml of saturated aqueous solution of sodium chloride (once), followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resultant residue to silica gel column chromatography to thus obtain 610 mg of the title compound from the fractions eluted with hexane-ethyl acetate (10:1). Yield=70%.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH:17]([C:19]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5H); 3.43-3.28 (m, 4H) and 2.00-1.81 (m, 4H).
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][C:50]([C@@H:53]2[CH2:58][CH2:57][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]2)=[C:49]2[C:44]=1[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]2>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:42][C:43]3[CH:52]=[CH:51][C:50]([C@@H:53]4[CH2:54][CH2:55][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:57][CH2:58]4)=[C:49]4[C:44]=3[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]4)[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c(=O)c(C)c[nH]c32)CC1
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (94.83 mg, 0.18 mmol) and ethyl cis-4-(5-amino-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Compound 304B, 70.0 mg, 0.213 mmol). 1H NMR (400 MHz, MeOD) δ ppm 8.57 (br. s., 1H), 8.32 (s, 1H), 7.82-7.88 (m, 2H), 7.48 (d, J=8.6 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 6.96 (dt, J=8.1, 2.2 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.05-4.13 (m, 4H), 3.91 (s, 3H), 3.35 (s, 1H), 3.33 (br. s., 1H), 2.92-3.03 (m, 1H), 2.51 (td, J=11.7, 3.4 Hz, 1H), 2.44-2.56 (m, 1H), 2.17 (br. s., 5H), 1.98 (d, J=10.1 Hz, 2H), 1.63-1.83 (m, 4H), 1.25-1.33 (m, 9H). MS (ES+): m/z:746.20/747.19 (100/40) [MH+]. HPLC: tR=4.44 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:22])=[O:23])[CH2:17][CH2:16]3)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(N2CCN(S(C)(=O)=O)CC2)n(C)c(=O)c1O
Product: Cn1c(N2CCN(S(C)(=O)=O)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[4-(methylsulfonyl)-1-piperazinyl]-6-oxo-4-pyrimidinecarboxamide was synthesized from 5-hydroxy-2-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester and 4-fluorobenzylamine as described in example to yield the title compound as a white solid 1H NMR (300 MHz, MeOD) δ: 8.88 (1H, t, J=5.9 Hz), 7.37 (2H, dd, J=8.6, 5.3 Hz), 7.05 (2H, t, J=8.8 Hz), 4.55 (2H, d, J=6.2 Hz), 3.55 (3H, s), 3.39–3.36 (4H, m), 3.26–3.23 (4H, m), 2.88 (3H, s). HRMS (M+H) calcd for C18H23FN5O5S: 440.14040. found: 440.1386.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>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]>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8](=[O:11])[NH:9][N:10]=3)[CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=c1[nH]nc2ccc(Br)cn12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 95 °C
Reaction time: 72 h

Procedure:
A mixture of 6.4 g 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (31.3 mmol), 12.4 g 4-(trifluoromethoxy)phenyl boronic acid (60.0 mmol), 12.4 g potassium carbonate (90.0 mmol), and 1.1 g Pd(dppf)Cl2 in 200 mL degassed 2:1:1 toluene:isopropanol:water was heated at 95° C. in sealed vessel. After 3 days, the aqueous layer was decanted and the organic concentrated. The residue was triturated with ethyl acetate to provide 6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a dark grey solid. m/z (ESI)=226.2 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 12.55 (s, 1H), 8.07 (s, 1H), 7.82 (d, 2H), 7.56 (dd, 1H), 7.43 (d, 2H), 7.33 (d, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.Cl.[F:17][C:18]1(F)[C:22](F)([F:23])[CH2:21][NH:20][CH2:19]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:12]([O:11][C:4]1[CH:3]=[C:2]([N:20]2[CH:21]=[C:22]([F:23])[C:18]([F:17])=[CH:19]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Reactant: FC1(F)CNCC1(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)Oc1cc(-n2cc(F)c(F)c2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
A suspension of 4-bromo-2-(tert-butoxy)-1-nitrobenzene (13.7 g), 3,3,4,4-tetrafluoropyrrolidine hydrochloride (9.87 g), Pd2(dba)3 (0.916 g), Xantphos (2.31 g) and sodium tert-butoxide (19.2 g) in 1,4-dioxane (150 mL) was stirred at 90° C. for 4 hr under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized from hexane/ethyl acetate to give the title compound (8.35 g).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[C:8]1([C:14]2[C:23]3[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][C:15]=2[C:28](OCC)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH3:2][C:1]1[N:3]=[C:28]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([C:14]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[O:5][N:4]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)n1
Yield: 85 %

Procedure:
A mixture of acetamidoxime (148 mg, 2.0 mmol) and powdered 4A molecular sieves (0.5 g) in THF (5 mL) is treated with 60% NaH in oil (80 mg, 2.0 mmol) for 15 min at ambient temperature. The reaction is treated with ethyl 4-phenyl-8-(trifluoromethyl)quinoline-3-carboxylate (173 mg, 0.50 mmol) and heated at reflux for 22 h. The reaction is cooled, concentrated, treated with water, and extracted with dichloromethane. The extracts are dried with MgSO4, concentrated, and the residue chromatographed with 20:80 ethyl acetate:hexane to afford the title compound as an off-white solid (151 mg). MS (ES) m/z 356.1; HRMS: calcd for C19H12F3N3O, 355.0932; found (ESI, [M+H]+), 356.1008.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)=[O:40])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc2ncnc(S(=O)c3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Yield: 168 %

Procedure:
To a stirring solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (120 mg, 0.25 mmol) from Example 46 in dichloromethane (2.5 mL) was added 3-chloroperoxybenzoic acid (56 mg, 77% max, 0.25 mmol). The reaction was quenched after 5 minutes with sat. NaHCO3(aq), extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) then repurified (12-100% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylsulfinyl)phenyl)urea (21 mg, 0.42 mmol, 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.16-9.12 (m, 2H), 8.33-8.28 (m, 2H), 7.49-7.34 (m, 4H), 6.50 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([CH3:24])[CH:23]=1)[N:20]=[CH:19][C:18]([C:25]([NH2:27])=[O:26])=[C:17]2[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1.[Br:37]C1C=C(S)C=CC=1>>[Br:37][C:8]1[CH:7]=[C:12]([S:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH3:24])[CH:23]=2)[N:20]=[CH:19][C:18]([C:25]([NH2:27])=[O:26])=[C:17]3[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Sc1cccc(Br)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(SCCCCCCCCCCCO)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4cccc(Br)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 58, using 3-bromothiophenol in place of 11-mercapto-1-undecanol. ES/MS calcd. for C24H21BrN3O2S+ 494.1. Found m/z=494.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH2:3]1.[CH:17]1[N:22]=[C:21](Cl)[C:20]2[N:24]=[CH:25][N:26]([C@@H:27]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]3[OH:35])[C:19]=2[N:18]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)(C)C.C(Cl)Cl.C(O)C>[OH:33][CH2:32][C@@H:30]1[C@@H:29]([OH:34])[C@@H:28]([OH:35])[C@H:27]([N:26]2[CH:25]=[N:24][C:20]3[C:19]2=[N:18][CH:17]=[N:22][C:21]=3[NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=3)[CH2:3]2)[O:31]1
Reactant: N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCN(c5ccc(C(F)(F)F)cn5)C4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 100 °C

Procedure:
267 mg 2-[(3R)-3-aminopyrrolidin-1-yl]-5-trifluoromethylpyridine, 331 mg 6-chloropurineriboside, 233 mg triethylamine, and 0.5 mL ethanol are combined and heated in a sealed vessel at 100° C. for about 5 hours. The mixture is cooled, partioned between methylene chloride (with some isopropyl alcohol added) and sodium bicarbonate. The organic layer is washed with brine, dried over magnesium sulfate, evaporated, and the residue purified by flash chromatography, eluting with 5% methanol in methylene chloride, to give (2R,3S,4R,5R)-2-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(R)-ylamino]purin-9-yl]tetrahydrofuran-3,4-diol, as the hemihydrate, m.p. 166-170° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][C@@H:5]([C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][C:13]=2[F:24])=[O:10])[CH2:4]1.[O:25]=[C:26]1[NH:31][C:30]2[N:32]=[C:33]([CH:36]=O)[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:11][C:9]([C@H:5]1[CH2:4][C@H:3]([CH2:2][NH:1][CH2:36][C:33]3[CH:34]=[CH:35][C:29]4[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=4[N:32]=3)[C@H:7]([OH:8])[CH2:6]1)=[O:10])=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(NC(=O)[C@H]3C[C@H](CN)[C@H](O)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(NC(=O)[C@H]3C[C@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 18.1 %

Procedure:
To a stirred solution of (±)-(1S,3R,4R)-3-(aminomethyl)-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide (0.43 g, 1.29 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.25 g, 1.29 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.41 g, 1.93 mmole). After 4 h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.12 g, 18%) as light yellow solid: 1H NMR (400 MHz, d8-dioxane), δ8.75 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.35 (m, 1H), 4.10 (s, 3H), 3.78 (s, 2H), 3.49 (s, 2H), 3.36 (m, 1H), 2.81 (m, 1H), 2.73 (m, 1H), 2.20 (m, 3H), 2.04 (m, 1H), 1.87 (m, 1H). LC-MS (ES) m/e 513 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1C=C(C(C)(C)C)[C:23](O)=[C:22]([C:31](C)(C)C)[CH:21]=1.CC1C=CC(C=[S:42])=CC=1>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[S:42][CH:23]=[C:22]([CH3:31])[CH:21]=1
Reactant: Cc1ccc(C=S)cc1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Product: COc1c(O)c(C(=O)C=Cc2cc(C)cs2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyidimethylmethyloxyacetophenone (starting material 1) and 4-methylthiobenzaldehyde according to general method 2 described earlier.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12](C1C=C(C(O)=O)C(=CC=1)C(O)=O)([O-:14])=[O:13]>[Cl-].[Zn+2].[Cl-]>[N+:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2][CH:11]=1)([O-:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Cc1ccc2ccccc2n1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=[N+]([O-])c1ccnc2ccccc12

Procedure:
Using a similar reactor as in Synthesis Example 1, chinaldine (14.3 parts), 4-nitrophthalic acid (21.1 parts), zinc chloride (13.6 parts) and ODB (100 parts) were charged, followed by refluxing for 2 hours under stirring. The reaction mixture was filtered, and the filter cake was thoroughly washed with water and then dried to obtain 4-nitroquinoline. In a similar manner as in Synthesis Example 1, the 4-nitroquinoline was reduced for amination, followed by amidation with 2-bromoisobutyric acid bromide to obtain a 2-bromoisobutyric acid substitute. This will be called “Quinoline-1”. In a similar manner as in Synthesis Example 3, the structure of Quinoline-1 was confirmed by NMR and IR. By HPLC, its purity was determined to be 91.0%. By an elemental analysis, the bromine content was found to be 16.5%. A maximum absorption wavelength was measured by the spectrophotometer, and as a result, λmax=445 nm. The structural formula is shown below.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O1CCCC1.CO.C[Si]([C:18]#[C:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)(C)C>O>[C:19]([C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: C[Si](C)(C)C#Cc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Under cooling in an ice bath, potassium carbonate (610 mg) was added to a tetrahydrofuran (30 mL) and methanol (70 mL) solution of 3-[(trimethylsilyl)ethynyl]benzenesulfonamide (11.1 g), and the obtained solution was then stirred at a room temperature for 12 hours. Thereafter, water was added to the reaction solution, and the solvent was then distilled away under a reduced pressure. Then, the residue was extracted with diethyl ether. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=2:1 to 1:1), so as to obtain the title compound (5.84 g) in the form of a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:23]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]([CH3:23])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)n[nH]1
Product: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)nn1C

Procedure:
Using methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate and iodomethane, and in the same manner as in Example 8, step B, the title compound was obtained.
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.[N:55]1[CH:60]=[C:59](B(O)O)[CH:58]=[N:57][CH:56]=1>>[CH3:44][C:28]1[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])=[N:30][C:25]([C:59]2[CH:60]=[N:55][CH:56]=[N:57][CH:58]=2)=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:27]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cncnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as off-white amorphous solid. MS: 496.2 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccn1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
Sodium hydride (105 mg, 2.24 mmol, 60% purity in mineral oil) was added in one portion to a stirred, ice/water-cooled solution of 1-tert-butoxycarbonylamino-1H-pyrrole-2-carboxylic acid methyl ester (448 mg, 1.86 mmol) and benzyl bromide (267 μL, 2.24 mmol) in DMF (8 mL); the mixture was stirred in the cold bath for 60 min, at which time TLC showed complete disappearance of starting material; then poured into diluted, cold ammonium chloride solution to quench, followed by extraction with EtOAc, then washed with water, and brine; the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was silica gel column purified to give the desired product (530 mg) as a clear oil. ESI (m/z): 353 (M+Na)+.