Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[F:28][C:29]([F:40])([F:39])[C:30]1([CH2:33]OS(C)(=O)=O)[CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:33][C:30]4([C:29]([F:40])([F:39])[F:28])[CH2:32][CH2:31]4)[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)c(F)c1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)c(F)c1

Procedure:
The title compound is prepared from 5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: C1N(CCO)CCN(CCS(O)(=O)=O)C1.[OH-].[Na+].[Mg+2].[Cl-].[Cl-].C(S)[C@@H](O)[C@H](O)CS.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP([O:91][P:92]([O:95][C@H:96]3[O:101][C@H:100]([CH2:102][OH:103])[C@@H:99]([OH:104])[C@H:98]([OH:105])[C@H:97]3[OH:106])([OH:94])=[O:93])(O)=O)[C@@H](O)[C@H]2O)C=1>>[CH2:102]([OH:103])[C@H:100]1[O:101][CH:96]([O:95][P:92]([OH:94])([OH:93])=[O:91])[C@H:97]([OH:106])[C@@H:98]([OH:105])[C@@H:99]1[OH:104]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: O[C@H](CS)[C@H](O)CS
Product: O=P(O)(O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h

Procedure:
Gal-1-Phospate uridyltransferase (UT): Two separate methods were used to measure UT activity in light of the near absence of activity in melon fruit. A continuous coupled enzyme assay modified from Elsevier and Fridovich-Keil (1996), J Biol Chem 271: 32002-32007, was carried out in a 0.5 ml reaction mixture containing 50 mM HEPES-NaOH (pH 7.8), 5 mM MgCl2, 0.5 mM DTT, 10 mM Gal-1-P, 1 mM NAD, 10 μM gl-1,6 bis P, 1 U G6PDH (from Leuconostoc), 2 U PGM, and enzyme sample. The reaction was initiated by 4 mM UDP-Glc and monitored for 10 min at 37° C. The amount of Glc-1-P produced was expressed as the amount of enzyme necessary to produce 1 μmol Glc-1-P per min at 37° C. Alternatively, a two-step end point assay, modified from Main et al. (1983), Physiol Plant 59: 387-392, was used for determining UT activity. The reaction buffer contained 25 mM HEPES-NaOH (pH 7.5), 1 mM EDTA, 5 mM MgCl2, 0.5 mM DTT with addition of 10 mM Gal-1-P and 10 μl of partially purified enzyme sample in a 100 μl reaction mixture. The reaction was initiated by 4 mM UDP-Glc and stopped after 10 min by boiling for 2 min and the mixture was cooled on ice. For the measurement of the Glc-1-P product 400 μl consisting of 50 mM HEPES-NaOH pH (7.8) 5 mM MgCl2, 1 mM NAD, 10 μM gl-1,6 bis P, 2 U PGM and 1 U G6PDH. After 40 min incubation at 30° C. , absorbance of NADH product was recorded at 340 nm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-])=O.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[C:7]3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3[nH]c(C(=O)O)c(-c4ccccc4)c3c2)cc1

Procedure:
The title compound was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene sulfonyl chloride followed the procedures of Example 1 Step 2 & Step 3 as a gray solid: 1H NMR (DMSO-d6) δ 1.25 (s, 9H, 7.05 (d, J=1.8 Hz, 1H, 7.10 (dd, J=8.9, 2.0 Hz, 1H, 7.26-7.45 (m, 6H, 7.54 (d, J=8.9 Hz, 2H, 7.57 (d, J=8.8 Hz, 2H, 9.81 (s, 1H, 11.79 (s, 1H, 12.42 (br s, 1H; MS (ESI) m/z 447 [M-H]−; HRMS calcd for C25H25N2O4S: 449.1533; found (ESI+): 449.1524; Anal. calcd for C25H24N2O4S.0.25H2O: C, 66.27; H, 5.45; N, 6.18. Found: C, 65.98; H, 5.34; N, 6.14.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([CH:20]2[CH2:22][CH2:21]2)=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl.O>[CH:20]1([C:5]2[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])=[CH:19][C:2]([NH:1][C:50]([C:46]3[O:45][CH:49]=[CH:48][CH:47]=3)=[O:51])=[C:3]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:27][CH2:28]3)[CH:4]=2)[CH2:21][CH2:22]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 5-amino-2-cyclopropyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 5b (66.0 mg, 0.14 mmol, 100 mol %) and N,N-diisopropylethylamine (0.07 ml, 0.42 mmol, 300 mol %) in dichloromethane (4.0 ml) was added furan-2-carbonyl chloride (0.02 ml, 0.21 mmol, 150 mol %) and a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred for 16 h at room temperature and then diluted with water and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford furan-2-carboxylic acid [4-cyclopropyl-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 5d (39.3 mg; 0.07 mmol, 49.7%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1[nH]c2ccccc2c1C(=O)C1C(C)(C)C1(C)C
Yield: 52.6 %

Procedure:
A mixture of 2-methylindole (0.75 g, 5.7 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.6 mL, 6.6 mmol), zinc chloride (1.0 M solution in Et2O, 6.6 mL, 6.6 mmol) and the product of Example 1A (6.3 mmol) in 15 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.76 g, 3.0 mmol, 52% yield). MS (DCI/NH3) m/z 256 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:12]([O:14][P:15](Cl)([O:17][CH2:18][CH3:19])=[O:16])[CH3:13].ClCCl.CO.[NH4+].[OH-].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].[O-][Mn](=O)(=O)=O.[K+]>O.ClCCl>[CH3:1][CH:2]1[CH2:4][N:3]1[P:15](=[O:16])([O:17][CH2:18][CH3:19])[O:14][CH2:12][CH3:13]
Reactant: CC1CN1
Reactant: CCOP(=O)(Cl)OCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)N1CC1C
Temperature: 5 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A 12 L 4-neck flask fitted with an overhead mechanical stirrer, temperature probe and 1 L pressure equalizing addition funnel was charged with 2-methylaziridine (300 g, 5.25 mol purchased from Menadiona SL of Barcelona, Spain), triethylamine (880 mL, 6.3 mol) and dichloromethane (3.0 L). The stirred solution was cooled to 5° C. and diethoxyphosphoryl chloride (804 mL, 5.51 mol) was added over 2.5 hours while maintain the internal temperature below 15° C. The reaction was then stirred for 18 hours, at which point the reaction was complete reaction was complete by TLC analysis (silica gel plate, 93:6:1 dichloromethane/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMnO4 stain). Water (3 L) was charged and the biphasic mixture was stirred for 20 minutes. The layers were separated and the organic layer was concentrated under reduced pressure. The remaining yellow oil was clarified by filtration. The filtrate (1028 g) was purified by short path vacuum distillation at 66-67° C., 1.0 mm Hg. to afford 2a as a colorless liquid (864.8 g, 85% yield, 99.0% GC purity). 1H NMR (300 MHz, CDCl3) δ 4.15 (dq, J=8.0, 7.1 Hz, 4H), 2.64-2.45 (m, 1H), 2.33 (ddd, J=17.9, 5.9, 1.3 Hz, 1H), 1.91-1.81 (m, 1H), 1.34 (dt, J=7.1, 0.9 Hz, 6H), 1.28 (dd, J=5.4, 1.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13]I>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cnc2ccccc2c1S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1c(N)cnc2ccccc12
Temperature: 40 °C
Yield: 97.8 %

Procedure:
17.62 g (0.1 mole) of 3-amino-4-quinoline-thiol are dissolved in 50 ml of a 2 molar sodium hydroxide solution, whereupon at a temperature below 40° C. 21.29 g (0.15 mole) of methyl iodide are added. The reaction mixture is stirred at 40° C. for an hour, extracted with chloroform, clarified with activated charcoal and evaporated. Thus 18.6 g of 3-amino-4-methylthio-quinoline are obtained, yield 94.6%, m.p.: 96°-98° C. (from methanol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A28 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), propane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 1.09 (t,3H), 1.90 (m,2H), 2.07 (m,4H), 2.95 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.57 (m, 2H), 5.67 (m, 1H), 7.87 (d,2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C19H25N5O7S2 499.12, found 500.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1.ClCCl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([N:12]1[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][CH2:11]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2)c1
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2C(C)=O)c1
Reaction time: 0.17 h

Procedure:
To a stir bar equipped flask containing 4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridne (1-5, 0.6 g, 0.19 mmol) was added dichloromethane (15 mL) followed successively by TEA (0.14 mL, 0.19 mmol), and acetic anhydride (0.06 mL, 0.59 mmol). The resulting solution stirred for 10 min. Water was added (2 mL), and then the reaction was washed with dichloromethane (2×30 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude reside was purified by reverse phase liquid chromatography (0.1% TFA) to give 1-acetyl-4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1-6). 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 1H), 6.96 (m, 4H), 6.82 (m, 1H); 6.36 (m, 1H), 6.20 (m, 1H), 3.82 (s, 3H), 3.80 (m, 2H); 3.40 (dt, J=11.9, 4.2 Hz, 1H); 2.74 (m, 1H); 2.42 (dd, J=16.0, 1.0 Hz, 1H), 2.20 (s, 3H); MS 344.1 found, 343.3 (M+H+) required.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:14]2([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:49]3[CH:48]=[CH:47][CH:46]=[C:45]([C:44]([F:55])([F:54])[F:43])[CH:50]=3)[C:15]2=[O:23])=[CH:25][C:26]=1[CH3:39]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3cccc(C(F)(F)F)c3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.710 g, 1.18 mmol), 3-(trifluoromethyl)phenylboronic acid (0.448 g, 2.36 mmol), copper (II) acetate (0.214 g, 1.18 mmol), triethylamine (0.41 mL, 2.36 mmol), 4 angstrom molecular sieves, and dichloromethane (20 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.812 g, 1.09 mmol), in THF (5 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (2.72 mL). Stir for 1 h. Add 1N aqueous HCl (10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.353 g (58%) of the title compound: mass spectrum (FAB): m/z=518(M+1); 1H NMR(DMSO-d6): δ8.25 (s, 2H), 7.84-7.79 (m, 4H), 7.33 (d, 1H), 7.26 (td, 1H), 7.14 (td, 1H), 6.85 (d, 1H), 6.75 (s, 4H), 2.07 (s, 12H).
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH:10]=[O:11])[CH2:4]1>C(O)C>[O:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][OH:11])[CH2:4]1
Reactant: O=CCC1CCCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCC1CCCOC1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A suspension of sodium borohydride (554 mg) in ethanol (20 ml) was cooled (ice bath) and a solution of tetrahydro-2H-pyran-3-ylacetaldehyde (1.88 gm) in ethanol (8 ml) added dropwise with stirring over 10 min. After 15 min the ice bath was removed and after a further 3 h the mixture was heated at 50° C. for 1 h. After cooling the solvent was evaporated and the residue treated with water and extracted three times with dichloromethane. The combined extracts were washed with dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title product as an oil. A further batch of product was obtained by acidifying the aqueous solution with 2N hydrochloric acid, saturating with sodium chloride and extracting three times with dichloromethane. These extracts were treated as above and the batches combined to give a total yield of 1.54 g (81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])[N:4]=1.[CH3:20]ON>CO>[CH3:20][C:12]1([O:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:13]1[CH:14]=[O:15]
Reactant: CON
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Solvent: CO
Product: COc1cc(OC)nc(OC2(C)C=CC=CC2C=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
In 100 ml of methanol, 5.2 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde and 1.0 g of methoxyamine were dissolved. The solution was stirred at room temperature for 2 hours. After the methanol was distilled out under reduced pressure, the resulting residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=10:1) to obtain 5.7 g of 0-methyl-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:29]([O:48][NH2:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:17][O:16][C:14](=[O:15])[CH:8]([CH2:9][CH2:10][C:11](=[O:13])[NH:49][O:48][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:18]
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(CCC(=O)O)CC(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 64 (1.10 g, 4.19 mmol) and HOBt (0.70 g, 5.03 mmol) in DMF (5 mL) were added O-trityl hydroxylamine (1.82 g, 6.28 mmol) and DIC (800 μL), respectively. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was partitioned between HCl (1N, excess) and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, saturated sodium bicarbonate, and brine. The solvent was evaporated following drying over sodium sulfate, and the crude was flashed with 20-30% ethyl acetate in hexanes. 1H-NMR(CDCl3, 400 MHz: 1.42(s, 9H); 1.58, 2.14, 2.47(3m, 7H); 3.69(s, 3H); 7.34(m, 15H); 7.88(d, broad, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[CH:6][C:5]=1[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC>O1CCCC1>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([NH:10][C:8]1[N:7]=[CH:6][C:5]2[CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCc2cc(NC(=O)C(C)(C)C)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl {4-(2-bromoethyl)-6-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}acetate (6.5 g, 16.3 mmol) in tetrahydrofuran (50 mL) cooled in a dry ice-acetone bath was treated with a solution of lithium diisopropylamide in tetrahydrofuran (50 mL) (prepared from diisopropylamine (3.79 g, 34.7 mmol) and n-butyllithium (2.5 M, 13.7 mL) dropwise via addition funnel over 1 h. After complete addition, the reaction stirred an additional 1 h, then was quenched with saturated sodium bicarbonate solution and allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate and water and transferred to a separatory funnel. The layers were separated and the aqueous extracted with ethyl acetate (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the resulting residue (2->25% EtOAc/hexanes eluent) provided the title compound. LC/MS (M+1)+=319.0.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)(=O)C>[CH3:5][C:6]1([C:12]2[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(Cl)Cl
Reactant: CC1(c2nnc(N)s2)CCCCC1
Solvent: CCOC(C)=O
Product: CC1(c2nnc(N=C=O)s2)CCCCC1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-(1-methylcyclohexyl)-2-amino-1,3,4-thiadiazole (6 grams) in ethyl acetate (100 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is filtered to recover the desired product 5-(1-methylcyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]O)=[CH:24][CH:23]=1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 62 %

Procedure:
To a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-ethoxybenzyl alcohol (0.36 g) and triphenylphosphine (0.62 g) in THF (10 ml) was added at 0° C. diisopropyl azodicarboxylate (0.47 ml), and the resulting mixture was stirred at room temperature for 3.5 days. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (279 mg) as colorless crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:12](=[O:15])[CH2:13]Cl)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C(O)(C(F)(F)F)=O>[OH:28][CH:17]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[CH2:16][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][C:12]1=[O:15]
Reactant: COc1ccccc1OCC(O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1OCC(O)CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL TFA. The mixture was allowed to stir at RT for 2 h. TFA was removed under reduced pressure. The residue was dissolved in 20 mL EtOH and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure to afford compound 13 which was used without further purification.