Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:27]=[C:26]([Cl:28])[N:25](COCC[Si](C)(C)C)[N:24]=3)=[O:22])=[C:16]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCO.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[C:37]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[N:27]=[C:26]([Cl:28])[NH:25][N:24]=2)=[O:22])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(Cl)n(COCC[Si](C)(C)C)n3)c(C3=CCCCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CCNCC2)cc1C1=CCCCC1)c1n[nH]c(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 63.3 mg, 0.102 mmol) in DCM (0.5 mL) and EtOH (11 μL) was added TFA (0.1 mL). After stirring the resulting mixture at RT for 12 h, another 0.1 mL of TFA was added. The reaction mixture was stirred for an additional 5 h at RT, the solvents were evaporated, and the title compound was purified by RP-HPLC (C18) eluting with 20-70% CH3CN in 0.1% TFA/H2O over 20 min to obtain the title compound (30 mg, 58%). 1H-NMR (CD3OD; 400 MHz): δ 8.14 (d, 1H, J=8.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1Hz), 7.13 (d, 1H, J=2.1Hz), 5.82 (br s, 1H), 3.45 (m, 2H), 3.19 (m, 2H), 2.98 (m, 1H), 2.28 (m, 4H), 2.14 (m, 2H), and 1.95-1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C20H24ClN5O, 386.1 and 388.1 (M+H), found 386.2 and 388.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([I:16])=[C:10]3[I:15])[C:6]=2[CH:17]=1.Br[C:19]1C=CC2OC(C)CN3C=CN=C3C=2C=1.IN1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH:13]([CH3:19])[CH2:12][N:11]3[C:10]([I:15])=[C:9]([I:16])[N:8]=[C:7]3[C:6]=2[CH:17]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)c(I)n1CCO2
Reactant: CC1Cn2ccnc2-c2cc(Br)ccc2O1
Agent: O=C1CCC(=O)N1I
Product: CC1Cn2c(nc(I)c2I)-c2cc(Br)ccc2O1

Procedure:
10-bromo-2,3-diiodo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was prepared similarly according to 9-bromo-2,3-diiodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene. 10-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with N-iodosuccinimide to afford 324 mg (90% yield) of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[Br:25][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=c1c2ccccc2nc(-c2ccc(CBr)cc2)n1-c1ccccc1

Procedure:
A 0.62 g quantity of 2-(4-methylphenyl)-3-phenyl-4(3H)-quinazolinone, 0.39 g of N-bromosuccinimide (NBS) and 0.05 g of benzoyl peroxide were suspended in 20 ml of benzene and refluxed with heating for 10 hours. After adding 50 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 2-(4-bromomethylphenyl)-3-phenyl-4(3H)-quinazolinone as light yellow crude crystals.
Reaction SMILES: C(OC([N:11]1C[C@H](O)C[C@H]1C(O)=O)=O)C1C=CC=CC=1.C(O[C:28]1[C:47]([O:48][CH3:49])=[CH:46][C:31]([C:32]([N:34]2[CH:38]=[C:37](CC(OC)=O)[CH2:36][C@H:35]2[CH2:44]O)=[O:33])=[C:30]([N+]([O-])=O)[CH:29]=1)C1C=CC=CC=1.NO.[N+](O)([O-])=O>C(Cl)(Cl)Cl>[CH3:49][O:48][C:47]1[C:46]2[N:11]=[CH:44][C@@H:35]3[CH2:36][CH2:37][CH2:38][N:34]3[C:32](=[O:33])[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])[C@H](CO)C1
Agent: NO
Solvent: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1N=C[C@@H]1CCCN1C2=O

Procedure:
Finely ground Cd/Pb couple (1.02 g). was added in small portions to a stirred solution of 100 (0.64 g, 1.51 mmol) in THF (10 mL) and 1M NH2OAc (10 mL). The reaction was followed by TLC (EtOAc), when no more starting material was observed, the mixture was poured into ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated to yield the product as a pale yellow oil (0.28 g, 80%): 1H NMR (270 MHz, CDCl3) δ 2.15 (m, 4H); 3.52 (m, 2H); 3.87 (s, 3H); 5.15 (m, 1H); 6.8-7.2 (m, 3H); 7.8 (d, J=4.7 Hz, 1H, imine H11). IR (Nujol): cm−1 3373, 2975, 1621, 1576, 1440, 1419, 1250, 1075, 750. MS: m/e (relative intensity) 230 (M+., 100), 215 (45), 201 (20), 187 (5), 160 (5), 146 (4), 133 (20), 105 (10), 76 (25), 70 (45), 63 (3), 51 (3). HRMS Calculated for C13H14N2O2: 230.1055. Found: 230.1055. [α]25D=+455.3° (c=0.6, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([O:8][C@H:9]2[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@@H:11]([S:12][CH3:13])[C@@H:10]2[NH:20][C:21](=[C:23]2[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]2=[O:32])[CH3:22])=[O:7])=[CH:4][CH:3]=1.[Si:35](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([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>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[Si:35]([O:19][CH2:18][C@H:15]1[O:14][C@@H:11]([S:12][CH3:13])[C@H:10]([NH:20][C:21](=[C:23]2[C:24](=[O:32])[CH2:25][C:26]([CH3:31])([CH3:30])[CH2:27][C:28]2=[O:29])[CH3:22])[C@@H:9]([O:8][C:6](=[O:7])[C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@@H:16]1[OH:17])([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CS[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A mixture of methyl 3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-1-thio-β-D-glucopyranoside (3) (1.00 g, 1.95 mmol), t-butyldiphenylsilylchloride (536 mg, 1.95) and 4-dimethylaminopyridine (238 mg, 1.95 mmol), in 1,2-dichloroethane (30 mL), was stirred under reflux for 6 hours. The reaction mixture was cooled to room temperature, diluted with chloroform (60 mL) and washed with diluted brine (3×50 mL, brine/water, 1:2), dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed using hexane—EtOAc 1:1 as the mobile phase to give a white solid, methyl 6-O(t-butyldiphenylsilyl)-3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1-thio-β-D-glucopyranoside (4) (1.1 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O.Cl>>[Cl:18][C:6]1[N:5]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)n2nc(C(F)(F)F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: Cc1cc(Cl)n2nc(C(F)(F)F)nc2n1

Procedure:
A mixture of 0.750 g (3.44 mmol) 5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol and 1.35 mL (14.46 mmol) of phosphorus oxychloride was heated under reflux for 60 minutes, during which time the pinkish solid dissolved gradually with the evolution of hydrogen chloride gas. The resultant dark red solution was distilled under reduced pressure to remove excess phosphorus oxychloride and the residue triturated with ice-water. The resultant aqueous solution was extracted with methylene chloride, the organic layer thus obtained was dried and the solvent was removed to give the desired product. Further washes of the crude residue with methylene chloride gave 0.547 g of 7-chloro-5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine. Yield 67.4%. The washed crude was used without purification in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([OH:23])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[Cl:31][C:32]1[C:33]([F:48])=[C:34]([CH:45]=[CH:46][CH:47]=1)[CH2:35][NH:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[NH:40]1)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:31][C:32]1[C:33]([F:48])=[C:34]([CH:45]=[CH:46][CH:47]=1)[CH2:35][NH:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[N:40]1[C:21](=[O:23])[CH2:20][N:13]1[C:14]2=[CH:15][N:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:8]([NH2:9])=[O:10])=[N:12]1)=[O:38]
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid trifluoroacetate salt (2.12 g, 6.35 mmol, prepared as described in Scheme A26) in DMF (32 mL) were successively added (1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide trifluoroacetate salt (2.70 g, 6.35 mmol), HBTU (3.37 g, 8.89 mmol) and DIPEA (4.44 mL, 25.4 mmol). The reaction mixture was stirred at RT for 16 h, and then was concentrated under vacuum. The residual oil was partitioned between CH2Cl2 and a sat. aq. NaHCO3 solution. A solid precipitated from the resulting emulsion and was filtered off, washed with water and dried under vacuum. The solid was suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. MS (LC/MS): 471 [M+H]+; tR (HPLC conditions c): 3.41 min.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.C1(C)C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:25]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 9 °C
Yield: 100.4 %

Procedure:
To 157.21 g (1 mol) of ethyl isonipecotate (A) were added 79.10 g (1 mol) of pyridine and 1 l of toluene. After cooling the mixture to 9° C., thereto was added dropwise 147.6 g (1.05 mol) of benzoyl chloride at 10° to 20° C. over 30 minutes with cooling. The reaction mixture was further stirred with cooling with ice for 1 hour and at room temperature for 1 hour. Then, thereto was added 500 ml of water to separate an organic layer. The organic layer was washed with 100 ml of water and 200 ml of a 5% aqueous solution of sodium hydrogencarbonate, succesively. Then, thereto was added 10 g of anhydrous magnesium sulfate. After drying, the solvent was removed by distillation to obtain 262.48 g of ethyl N-benzoylisonipecotate (B). The NMR spectrum of the obtained compound was measured. The result is shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([OH:14])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:14][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:7]=[C:8]([O:10][CH:11]([CH3:12])[CH3:13])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(OC(C)C)c1
Yield: 99.7 %

Procedure:
To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (7.00 g, 33.3 mmol) in acetone (80 mL) was added K2CO3 (5.06 g, 36.6 mmol) and 1-fluoro-4-nitrobenzene (3.53 mL, 33.3 mmol) at rt. The resulting mixture was refluxed for 12 hr. Then the mixture was filtered through a pad of Celite to remove insoluble salts and the cake was rinsed with acetone. Combined filtrates were concentrated under vacuum to afford a residue which was purified by silica gel flash chromatography (7.5×30 cm, hexane/EtOAc, v/v 10:1, 5:1). Fractions containing the mono-alkylation product were pooled and concentrated to give 3-isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester (11.0 g, 44%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=9 Hz, 2H), 7.43 (dd, J=1, 2 Hz, 1H), 7.29 (dd, J=1, 2 Hz, 1H), 7.04 (d, J=9 Hz, 2H), 6.80 (dd, J=2, 2 Hz, 1H), 4.56-4.64 (m, 1H). 3.90 (s, 3H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH:10](OCC)=[O:11]>>[CH:10]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:11]
Reactant: CCOC=O
Reactant: NCCN1CCOCC1
Product: O=CNCCN1CCOCC1
Yield: 100 %

Procedure:
The procedure of B. V. Cheney et al. [J. Med. Chem., 28, 1853-1864 (1985)) was used. A solution of 4-(2-aminoethyl)morpholine (1.00 g, 76.8 mmol) and ethyl formate (213 mL, 2640 mmol) was refluxed overnight under an atmosphere of nitrogen. Vacuum distillation gave 1.46 g (100% yield) of a clear, colorless liquid (bP0.3 18°-120° C.). The 1H NMR spectral data were consistent with the structure of the title compound.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([SH:27])([CH3:26])[CH3:25]>>[C:24]([S:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])([CH3:25])[CH3:23]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)S
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1SC(C)(C)C
Temperature: 100 °C
Yield: 26 %

Procedure:
Prepared similarly to that described in Example 127 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 74 mg, 0.250 mmol) and 2-methylpropane-2-thiol (67.6 mg, 0.749 mmol; Acros, Geel, Belgium), heating at 100° C. for 7 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(3-(tert-butylthio)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (s, 9H) 2.59 (s, 3H) 2.83 (t, J=6.85 Hz, 2H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 6.93 (d, J=2.15 Hz, 2H) 7.63 (t, J=7.63 Hz, 1H) 7.80-7.88 (m, 2H) 11.50 (br. s., 1H). MS (ESI, pos. ion) m/z: 367.1 (M+1).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][C:16]1[S:17][C:18]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][N:20]=1)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:29][O-].[Na+].CBr>CO.O>[C:1]([NH:11][CH2:12][C:13]([N:15]=[C:16]1[N:20]([CH3:29])[N:19]=[C:18]([S:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:17]1)=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1nnc(SCc2ccccc2)s1
Reactant: C[O-]
Agent: CBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1nc(SCc2ccccc2)sc1=NC(=O)CNC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of the product from Example VIII (ca 30 gm, 0.1 mole) in methanol (200 ml)m containing sodium methoxide (from 2.5 g sodium, 0.11 mole) is warmed in a flask fitted with a Dry Ice condenser, stirred 3 hr., then cooled to 5° C. Methyl bromide gas was then passed through the reaction (0.15 mole) and the solution stirred overnight at room temperature. The solution is diluted with water (200 ml) to give a sticky solid, ca25 gm. this is slurried with cold concentrated sodium hydroxide solution to remove starting material Yield 20 gm, 40%, recrystallized from ethanol, 15 gm, m.p. 92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:27])[C@@H:17]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].I[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][C:16](=[O:27])[C@@H:17]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1
Reactant: C#CCOc1ccc(CCNC(=O)[C@@H](NS(=O)(=O)CC)C(C)C)cc1OC
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2cccs2)c(OC)c1)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2 g of (S)-2-(ethylsulfonyl-amino)-3-methyl-butyric acid N-[2-(3-methoxy-4-propargyloxy-phenyl)-ethyl]-amide, 2.1 g of 2-iodothiophene and 2 ml of triethylamine are heated to 40° C. in 50 ml of chloroform. 70 mg of bis(triphenylphosphine)palladium(II) chloride and 32 mg of copper(I) iodide are added thereto. The reaction mixture is stirred for one hour at 60° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(Cl)nc2)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 6-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=33%).
Reaction SMILES: [CH2:1]([OH:17])[CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(O)C([OH:34])CCCCCCCCCCCCCC.C(O)C(O)CCCCCCCCCCCCCCC.[CH2:55]([OH:74])[CH:56](O)[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72].P(O)(OC)OC>CO>[CH:1]([OH:17])([OH:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH:55]([OH:74])([OH:16])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72]
Reactant: CCCCCCCCCCCCCC(O)CO
Reactant: CCCCCCCCCCCCCCCCC(O)CO
Reactant: CCCCCCCCCCCCCCC(O)CO
Agent: CCCCCCCCCCCCCCCC(O)CO
Agent: COP(O)OC
Solvent: CO
Product: CCCCCCCCCCCCCCC(O)O
Product: CCCCCCCCCCCCCCCCCC(O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Approximately 360 g of the 1,2-mixed pentadecanedioloctadecanediol (obtained from Viking Chemical Co. as Vikol 158 containing about 28% 1,2-pentadecanediol, about 28% 1,2-hexadecanediol, about 28% 1,2-heptadecanediol and about 16% 1,2-octadecanediol) were charged to a glass reactor equipped with heater, agitator, Dean-Stark tube with condenser and provision for blanketing the vapor space with nitrogen. The contents were heated to 70° C. to liquify and 55 g of dimethyl hydrogen phosphite were slowly added. The reaction mixture was heated to 110° C. and held for 2 hours, held at 120° C. for 1 hour, and held at 130° C. for 1 hour. During this reaction period, methanol distilled over and condensed into the trap. The crude product was vacuum stripped at 150° C. to remove volatile materials. 379 g of finished additive were produced. The product was an amber fluid which became waxy on cooling.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.[CH2:35]([N:37](CC)CC)C>>[C:35]([CH:22]1[CH2:21][O:20][CH:19]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:33])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)[CH2:24][CH2:23]1)#[N:37]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCN(CC)CC
Agent: Cl
Product: N#CC1CCC(n2nc(-c3cccc(NC(=O)c4cccnc4)c3)c3ccccc32)OC1
Yield: 54 %

Procedure:
The title compound was prepared according to the procedure described in 225 A, using 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.300 g, 0.94 mmol), nicotinoyl chloride hydrochloride (0.334 mL, 1.88 mmol), and triethyl amine (0.655 mL, 4.7 mmol). The title product was purified by column chromatography (SiO2, 5% methanol in dichloromethane) (0.215 g, 54% yield): ES-MS (m/z) 424 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH:15]=[CH2:16])[CH2:13][O:12][C:11](=[O:14])[O:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:14]=[C:11]1[O:10][CH2:9][C:8]([CH:15]=[CH2:16])([C:6]([OH:7])=[O:5])[CH2:13][O:12]1
Reactant: C=CC1(C(=O)OC(C)(C)C)COC(=O)OC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1(C(=O)O)COC(=O)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of 2-oxo-5-vinyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester (200 mg, 0.88 mmol) in dichloromethane (4 mL) was stirred at 0° C. Trifluoroacetic acid (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. The solvent was evaporated and the residue was triturated with diethyl ether/iso-hexanes (1:1) to afford the title compound (135 mg, 90%) as a white solid. 1H NMR (300 MHz, d6-DMSO) 64.51 (d, J=10.5 Hz, 2H), 4.67 (d, J=10.5 Hz, 2H), 5.38 (d, J=17.6 Hz, 1H), 5.43 (d, J=10.7 Hz, 1H), 5.83 (dd, J=17.6, 10.7 Hz, 1H), 13.5-14.0 (br s, 1H). LCMS (m/z) 173.2 [M+H], Tr=0.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[CH3:31][C:32]([NH2:36])([CH3:35])[CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:36][C:32]([CH3:35])([CH3:31])[CH2:33][NH:34][C:27]([C:24]1[CH:25]=[CH:26][C:18]2[C:17]3[S:30][C:14]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:12](=[O:13])[NH:11][N:10]=4)=[CH:15][C:16]=3[CH2:22][CH2:21][O:20][C:19]=2[CH:23]=1)=[O:29]
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: CC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(N)CNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 332 as a colorless solid after reverse phase HPLC. MS: (ESI+) 510.0