Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4].[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2.C([O-])([O-])=O.[Na+].[Na+]>C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>[NH:1]([C:21]([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: NCC(=O)N1CCC[C@H]1C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCC(=O)N1CCC[C@H]1C(=O)N1C[C@H](O)C[C@H]1C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 4 °C
Reaction time: 21 h

Procedure:
Fmoc-Gly-Pro-Hyp was synthesized from Gly-Pro-Hyp as follows: 3.0 g Gly-Pro-Hyp (10.5 mmol) was dissolved in 54 mL Na2CO3 --H2O (1:9) and stored at 4° C. 4.05 g 9-fluorenylmethyl succinimidyl carbonate (12.0 mmol) was dissolved in 45 mL dimethoxyethane and stirred at 4° C. The aqueous Na2CO3 solution was added slowly to the dimethoxyethane solution, and the reaction proceeded for 2.5 h at 4° C. and 21 h at room temperature. The solution was filtered, and 360 mL H2O was added to the filtrate. The aqueous layer was extracted with 300 mL of diethyl ether, acidified to pH 2 with concentrated HCl, reduced to half volume at 80° C. under reduced pressure, and stored at 4° C. for 24 h. The aqueous layer was decanted from the oily precipitate, reduced to ~30 mL at 81° C. under reduced pressure, and stored at 4° C. for 24 h. The aqueous layer was decanted from the oily precipitate. Both oily precipitates were dissolved in a total of 20 mL methanol, then 250 mL ethyl acetate was added. A white residue was recovered by evaporation at 73° C. for 1 h under reduced pressure; yield 3.23 g (6.39 mmol, 60.6%). The identity of the product as Fmoc-Gly-Pro-Hyp and its homogeneity was verified by thin layer chromatography [chloroform-methanol-HOAc (95:20:3)], scanning UV spectroscopy, and Edman degradation sequence analysis.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH:22]1[C:26]2([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][C:26]2([N:22]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:23][CH2:24][CH2:25]2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2)CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN2C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (851325-42-3) in the presence of TBTU and DIEA to obtain the title compound as yellow oil; MS (EI): m/e=507.6 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH:22]=[CH:26][N:27]([CH3:29])[CH3:28])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine (11.85 g, 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL) was stirred at reflux for 17 h. The mixture was cooled to room temperature and then to 0° C. The resulting orange precipitate was collected by filtration, washed with cold hexanes, and dried under vacuum to afford the title compound as an orange solid, 10.17 g (73%). 1H NMR (d6-DMSO) δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H), 7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d, 1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray) 377 (80), (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[C:33]([C:35](OC)=[O:36])[CH:32]=[C:31]([C:39]([O:41][CH3:42])=[O:40])[CH:30]=1)=[O:28]>O1CCCC1>[CH3:42][O:41][C:39]([C:31]1[CH:32]=[C:33]([CH:34]=[C:29]([C:27]([O:26][CH3:25])=[O:28])[CH:30]=1)[C:35]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:36])=[O:40]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cc(C(=O)OC)cc(C(=O)OC)c2)n1
Yield: 14.2 %

Procedure:
Under the conditions of example 1B, 1 g of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl)-pyridine in 10 ml of tetrahydrofuran is mixed with 4.26 ml of n-butyllithium (1.6 molar in hexane) and 807 mg of 1,3,5-benzenetricarboxylic acid trimethylester in 6 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 203 mg of oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP 18 material) with methanol/H2O=9:1. 74 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:8])[CH3:7].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].O>CCOCC>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])=[O:20])([CH3:8])[CH3:7]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
n-Butyllithium (2.5M, 100 mL) was added with stirring under nitrogen at 0°-5° C. during ten minutes to a solution of 2-isopropylbromobenzene in anhydrous ether (500 mL). The mixture was allowed to warm to room temperature, stirred at room temperature for six hours, and cooled to -60° C. A solution of diethylcarbamyl chloride (34 g) in anhydrous ether (50 mL) was added during 20 minutes while maintaining the temperature below -50° C. The temperature was allowed to rise to room temperature during one hour. Water (100 mL) was added. The ether layer was washed with saturated aqueous sodium chloride (200 mL), dried over magnesium sulfate and stripped of ether. Distillation of the residue (80°-90° C./0.1 mm Hg) gave 2-isopropyl-N,N-diethylbenzamide (44 g, 80% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Yield: 96 %

Procedure:
Saponification of intermediate 14, ethyl 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.225 g, 0.65 mmol) as described in the preparation of intermediate 7 gave 0.198 g (96% yield) of the title acid as white crystals; mp 167–168° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ ppm: 1.68 (3H, d, J=6.6 Hz, CH3), 3.93 (2H, m, CH2), 4.12–4.21 (1H, m, CH), 4.27–4.35 (1H, m, CH), 4.70 (1H, q, J=6.6 Hz, OCH), 5.53 (2H, ABq, JAB=11.1 Hz, OCH2), 7.39 (3H, m, aromatics), 7.55 (2H, m, aromatics). MS (ESI+) m/z 317 [M+H+]. Anal. Calcd for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C 60.65; H, 5.05; N, 8.72.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:21]([OH:26])[OH:22])=[CH:3][C:4]=2[CH:9]=1
Reactant: c1csc(Cc2ccc3occc3c2)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(Cc3nccs3)ccc2o1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of 2-(benzofuran-5-ylmethyl)thiazole (0.68 g, 3 mmol) in THF (20 mL) was cooled to −78° C. (under argon), treated with 2.5 M n-BuLi (3.0 equiv, 3.6 mL, in hexanes), and stirred for 2 min, warmed to 0° C. for 30 min, cooled to −78° C., and treated with triisopropyl borate (1 mL, 6 mmol). After 5 min, cooling was removed and the mixture slowly warmed to room temperature and stirred for 2 h. The mixture was diluted with EtOAc, washed 1× with brine, dried over MgSO4 and evaporated to give 5-(thiazol-2-ylmethyl)benzofuran-2-ylboronic acid as a yellow solid. MS (ESI) m/z: Calculated: 259.1; Observed: 260.4 (M++1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:19][NH2:20]>>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH:9]=1)[C:3]([NH:19][NH2:20])=[O:2]
Reactant: COC(=O)c1cc(N)ccc1Oc1ccccc1
Reactant: NN
Product: NNC(=O)c1cc(N)ccc1Oc1ccccc1
Yield: 76 %

Procedure:
A mixture of phenol (5.64 g, 60 mmol) and potassium t-butoxide (6.74 g, 60 mmol) in 50 mL 1,4-dioxane was stirred at room temperature for 0.5 h. To the mixture was added 2-chloro-5-nitro-benzoic acid methyl ester (10.78 g, 50 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography with EtOAc:hexanes, 1:4, as eluant, yielding (11.739 g, 86%) 5-nitro-2-phenoxy-benzoic acid methyl ester. A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (2.0 g, 7.32 mmol) in 30 mL ethanol and Pd/C (200 mg) were hydrogenated at 40 psi overnight to yield 5-amino-2-phenoxy-benzoic acid methyl ester (1.672 g, 94%). A mixture of 5-amino-2-phenoxy-benzoic acid methyl ester (0.95 g, 3.9 mmol) and hydrazine (4 mL, 80%) was refluxed for 4 h to yield 5-amino-2-phenoxy-benzoic acid hydrazide (0.722 g, 76%). The title compound was prepared from 5-amino-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (CDCl3): 10.81 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.40 (m, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8, 2H), 6.80 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: BrCc1ccccc1
Reactant: O=C1CCOc2cc(O)c(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCOc2cc(OCc3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 6-fluoro-7-hydroxychroman-4-one (the compound of Preparation 29, 0.93 g, 5.11 mmol), benzyl bromide (0.61 mL, 5.13 mmol), potassium carbonate (1.41 g, 10.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The mixture was cooled, filtered, and concentrated to a yellow solid. This residue was recrystallized from ethyl acetate/ether to give 1.02 g (73%) of 6-fluoro-7-benzyloxychroman-4-one in two crops as cream white crystals which had: mp 155-156° C.; NMR δ 7.58 (d, J=11 Hz, 1 H), 7.46-7.33 (m, 5 H), 6.54 (d, J=6.7 Hz, 1 H), 5.16 (d, 2 H), 4.50 (t, J=6.4 Hz, 2 H), 2.75 (t, J=6.4 Hz, 2 H). Analysis calculated for C16H13FO2 : C, 70.58; H, 4.81. Found: C, 70.45; H, 4.80.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=N[CH:7]=1.Br[C:18]1C=CC(F)=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[CH:18][CH:7]=1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(-n2cnc3cnccc32)cc1

Procedure:
Intermediate 7 was prepared in a manner analogous to Intermediate 1, substituting 1-bromo-4-fluorobenzene for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C12H8FN3, 213.07; m/z found 214.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][CH2:23][CH3:24].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][CH2:23][CH3:24]
Reactant: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OC)CC2)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)O)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
Methyl trans-4-(4-chloro-3-(ethylamino)phenylsulfonamido)cyclohexane-carboxylate (Intermediate 12, 220 mg, 0.552 mmol) in 1/1/1 THF/MeOH/1N LiOH was warmed to 45° C. overnight. The reaction was cooled to room temperature, then acidified to pH 3 with 1N HCl and extracted with multiple volumes EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as colorless solid (169 mg, 0.468 mmol, 85% yield). MS MH+ 361.2
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[C:13](=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To the solution of N-benzyloxycarbonyl-4-ethoxycarbonylpyrrolidin-3-one (291 g) in acetone (1.5 l) was added potassium carbonate (200 g), followed by iodomethane (300 mL), and then the solution was refluxed for 3 hr. The reaction mixture was cooled at room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:6) to obtain the desired compound, (237.7 g, 80.7%).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]12[CH2:8][OH:9].[OH-:10].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[OH:10][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:1]
Reactant: OCC12CCCCC1O2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCC1(O)CCCCC1O

Procedure:
A stirred mixture of 10.6 g of 1,2-epoxycyclohexanemethanol and 8 drops of concentrated sulfuric acid in 100 ml of p-dioxane and 100 ml of water was heated at 60°-70° for 18 hours. The reaction mixture was neutralized with sodium hydroxide, and evaporated under reduced pressure to a viscous residue. The residue was taken up in methanol and dried with sodium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to a residue. The residue was distilled to give 10.8 g of 1,2-dihydroxycyclohexanemethanol; bp 170°-240°/0.02 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+].[SH:29][C:30]1[S:31][C:32]([CH3:35])=[N:33][N:34]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:30]3[S:31][C:32]([CH3:35])=[N:33][N:34]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 2.72 g. (0.01 mole) of 7-ACA in 50 ml. of 0.1 M, pH 6.4 phosphate buffer, was added 1.68 g. (0.02 mole) of NaHCO3 followed by 1.45 g. (0.011 mole) of 2-mercapto-5-methyl-1,3,4-thiadiazole and the mixture heated and stirred at 60° C. for five hours. The resulting slurry was then allowed to cool to about 22° C. over a one hour period. The crystalline precipitate was collected by filtration, washed with water and air dried. Yield 1.3 g., dec. pt. 206° C. Scaling up the reaction 10X gave 18.0 g.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[CH3:10][N:11]1[C:16](=[O:17])[C:15]2=[C:18]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([OH:37])=[O:36])[N:19]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[N:20]=[C:14]2[NH:13][C:12]1=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][C:4]1[C:3]([CH2:2][N:13]2[C:14]3=[N:20][N:19]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[C:18]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])=[C:15]3[C:16](=[O:17])[N:11]([CH3:10])[C:12]2=[O:41])=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Temperature: 85 °C
Reaction time: 20 h

Procedure:
4-(chloromethyl)-3,5-dimethylisoxazole (0.145 g) was added to a suspension of Resin bound 3-[5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.120 g) and potassium carbonate (0.397 g) in dimethylformamide (1 ml). Reaction mixture was shaken at 85° C. for 20 hours. The resin was filtered and washed (3 times) DMF, H2O, DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum to give the subtitle compound.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([CH:12]=O)=[CH:11][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][NH:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:21][NH:22][C:23](=[O:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:12][C:10]3[CH:9]=[C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:20])[NH:4][C:5]=4[CH:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(-c5ccccc5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 349A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.82 Hz, 3H) 2.51-2.57 (m, 4H) 2.73 (d, J=4.55 Hz, 3H) 3.18-3.29 (m, 4H) 3.48 (s, 2H) 4.70 (q, J=6.65 Hz, 1H) 6.90-6.96 (m, 4H) 7.32-7.37 (m, 1H) 7.41-7.46 (m, 2H) 7.51-7.56 (m, 2H) 7.66-7.72 (m, 2H) 8.13 (q, J=4.38 Hz, 1H) 10.71 (s, 1H). ESI-MS: m/z 471.4 (M+H)+. mp=184.9-188.9° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1O

Procedure:
4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid (1.98) was prepared from 5-bromosalicylic acid (2.6 g, 11.9 mmol ) and 4-nitrophenylboronic acid (3.0 g, 17.9) following general procedure D
Reaction SMILES: [I-].[Na+].C([O-])(O)=O.[Na+].Cl[CH:9]([CH3:27])[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=1)=[O:11]>CC(C)=O>[CH3:27][CH:9]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:14][CH2:13][NH:12][C:10]1=[O:11]
Reactant: CC(Cl)C(=O)NCCNc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1C(=O)NCCN1c1cccc(OC(F)(F)F)c1
Yield: 66.1 %

Procedure:
Sodium iodide (64 mg, 0.43 mmol) and NaHCO3 (86 mg, 1.03 mmol) were added to a solution of 2-chloro-N-[2-(3-trifluoromethoxy-phenylamino)-ethyl]-propionamide (266 mg, 0.86 mmol) in acetone (20 mL). The reaction mixture was heated at reflux for 72 h, then evaporated. The residue was partitioned between EtOAc and water. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc gradient) afforded the title compound (156 mg, 66%). Yellow oil, MS: 275.1 (M+H)−.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:33]3[C:28](=[C:29]([N+:35]([O-])=O)[C:30]([CH3:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Fe].C(O)C.O>[NH2:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[C:33]2[C:28]=1[CH:27]=[CH:26][N:25]=[C:24]2[NH:23][C:20]1[CH:21]=[CH:22][C:3]([Cl:2])=[C:4]([CH:19]=1)[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: Cc1ccc2c(Nc3ccc(Cl)c(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)nccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(Nc3ccc(Cl)c(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)nccc2c1N
Yield: 71.6 %

Procedure:
Iron (257 mg, 4.145 mmol) and concentrated hydrochloric acid (0.03 mL) were added to ethanol/water (10 mL/10 mL), and refluxed for 1 hour. The mixed reaction solution was added with tert-butyl 4-(2-chloro-5-((6-methyl-5-nitroisoquinolin-1-yl)amino)benzyl)piperazine-1-carboxylate (424.5 mg, 0.829 mmol) obtained in <Step 3> above, and refluxed for 3 hours. The reaction mixture was filtered a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol=3/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:3→1:2 (v/v)) to obtain the title compound (286 mg, 72%).
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[Na].[CH2:18]([S:22][O-])[CH:19]([CH3:21])[CH3:20]>C1C=CC=CC=1>[CH2:18]([S:22][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CBr
Reactant: CC(C)CS[O-]
Agent: [Na]
Solvent: c1ccccc1
Product: CC(=CCOc1ccc2c(c1)OCO2)CSCC(C)C

Procedure:
A solution of 4.3 g (0.015 mol) of 5-(4-bromo-3-methyl-2-butenyloxy)-1,3-benzodioxol in 50 cc of benzene is added at 25° to 1.7 g (0.015 mol) of sodium-isobutylthio alcoholate in 30 cc of benzene. The mixture is kept at reflux temperature for 13 hours, is subsequently filtered, washed with saturated salt solution and evaporated. The remaining yellow oil is chromatographed with hexane/ethyl acetate 7:1 on silica gel, whereby colourless 5-(4-isobutylthio-3-methyl-2-butenyloxy)-1,3-benzodioxol is obtained. nD20 = 1.5463.