Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: Brc1ccc(Br)nc1
Product: COc1ccc(COc2ccc(Br)cn2)cc1

Procedure:
Synthesized as described in Example 53A from 2,5-dibromopyridine and p-methoxybenzyl alcohol with the following exceptions: the reaction was heated at reflux for 90 min, and the title compound was purified by flash chromatography (EtOAc/hexanes): 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J=2.6, 0.6 Hz, 1H), 7.64 (dd, J=8.8, 2.6 Hz, 1H), 7.38 (m, 2H, AA′XX′), 6.91 (m, 2H, AA′XX′), 6.69 (dd, J=8.9, 0.6 Hz, 1H), 5.26 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [N:1]([C:4]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:19]([OH:20])=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36]
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate (14.63 g, 30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (2.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 6 h at ambient temperature. After the insoluble matter was filtered off, the solvent was concentrated in vacuo to give the crude product (7.58 g, 90% yield), which was used directly in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: CNOC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of 2-bromo-5-fluorobenzoic acid (2.0 g, 9.13 mmol) in DCM (90 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (1.069 g, 10.96 mmol), N-(3-dimethylaminopropyl)-K-ethylcarbodiimide hydrochloride (2.276 g, 11.87 mmol), hydroxybenzotriazole (1.818 g, 11.87 mmol) and triethylamine (2.55 mL, 18.26 mmol). The resulting mixture was stirred at room temperature for 5.5 h after which time the reaction was quenched by addition of sat. aq. NaHCO3 solution and the layers separated. The organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Hexanes) to afford 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (dd, J=8.8, 4.9 Hz, 1H), 7.05 (dd, J=8.2, 3.0 Hz, 1H), 7.00 (td, J=8.4, 3.0 Hz, 1H), 3.50 (s, 2H), 3.38 (s, 3H).
Reaction SMILES: CC(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=O)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC1CCC(O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1CC[C@H](O)CC1

Procedure:
Tert-butyl ((1r,4r)-4-hydroxycyclohexyl)methylcarbamate (1 g) in dichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL) at 0° C. for 10 minutes and at room temperature for 30 minutes. The reaction mixture was concentrated and dried in vacuo to provide the title compound as a trifluoroacetic acid salt.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6]O[C:4]([C:16]([OH:18])=[O:17])=[CH:3]1.[NH4+:19].[OH-].Cl>>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:19][C:4]([C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 3 h

Procedure:
300 g (1.22 mol) of 4-oxo-5-(phenylmethoxy)-4H-pyran-2-carboxylic acid was put into a flask and 5 1 of 33% NH4OH was carefully added with stirring. The reaction mixture was then stirred under reflux. After 3 hours, one additional liter of 33% NH4OH was added slowly. Stirring was continued for further 2 hours under reflux. The reaction solution was then evaporated until the product crystallized. The product was transferred back into the reaction flask and water added until a clear solution was obtained (approximately 5 1, pH 6.38). This solution was stirred vigorously while concentrated hydrochloric acid was added dropwise until a pH of 3 was obtained. The precipitated white product was removed by filtration, thoroughly washed with water and dried. Yield: 273 g (1.12 mol)=91.8%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([N:9]2[CH2:15][CH2:14][C:13]3[C:16](O)=[N:17][CH:18]=[N:19][C:12]=3[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:25]>CC#N.CCOC(C)=O>[Cl:25][C:16]1[C:13]2[CH2:14][CH2:15][N:9]([C:4]3[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11][C:12]=2[N:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccnc1N1CCc2ncnc(Cl)c2CC1
Temperature: 90 °C
Yield: 33 %

Procedure:
To a solution of 7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (185 mg, 0.60 mmol) in CH3CN (2 mL) was added POCl3 (0.11 mL, 1.19 mmol). The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc, and quenched slowly with saturated (satd.) aq. NaHCO3. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (65 mg, 33%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([O:23]CC)=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([OH:23])=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CC(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
To a solution of compound 118E (128 mg, 0.33 mmol) in THF (15 mL) was added 0.1 M aqueous LiOH (3.75 mL) and the mixture was stirred at room temperature. After 24 h, the resultant solution was acidified to pH 4 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (20 mL) and concentrated to give the crude product, which was further purified by chromatography on 70-230 mesh silica gel eluted with CH2Cl2:methanol:water 40:10:1 to afford 104 mg (0.29 mmol, 88%) of the product as a solid, mp 206-207° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.05 (s, 3H), 3.81 (s, 2H), 7.65 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 24.8, 37.3, 119.0, 127.5, 137.9, 142.6, 153.3, 169.4, 169.5, 170.9; MS (LCQ, ESI+) Calcd for C12H13N4O5S2 357.0. found 357.0 (M+H)+; HRMS (ESI+, m/z) Calcd for C12H13N4O5S2 357.0327. found 357.0326 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=3)[CH:4]=[N:5]2)=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: O=Cc1ccc2[nH]ncc2c1F
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1F

Procedure:
[4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-carbaldehyde was prepared from 4-fluoro-1H-indazole-5-carbaldehyde and 4-chloro-2-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: Clc1cccc(I)c1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(Cl)c4Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.68-6.94 (m, 12H), 6.68 (d, 1H, J=2.8 Hz), 3.69 (s, 2H), 3.15-3.02 (m, 2H), 2.54-2.42 (m, 2H), 2.18-2.02 (m, 2H), 1.88-1.76 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 520.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[Cl:22])[C:5]([N+:23]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.C(O)C.[Fe]>[NH2:23][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[Cl:22])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 6-bromo-2-[N-(2-chloro-4-phenylbenzyl)-amino]-3-nitropyridine (13.5 g) in acetic acid (27 ml) and ethanol (81 ml) was added iron powder (7.2 g) at room temperature under a nitrogen flow, and the mixture was refluxed under heating. After 2 hr, the reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated and subjected to azeotropic distillation twice with toluene. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue and the mixture was stirred at room temperature for 10 min. This mixture was filtered through celite and washed with ethyl acetate. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 400 ml) and eluted with hexane:ethyl acetate=5:1-3:1-2:1 to give 3-amino-6-bromo-2-[N-(2-chloro-4-phenylbenzyl)amino]pyridine (10.6 g) as a black gum.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH:4]1[CH2:15][N:14]2[C:6]([C:7]3[NH:8][C:9]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:10][C:11]=3[N:12]([CH2:17][CH2:18][CH3:19])[C:13]2=[O:16])=[N:5]1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CS(C)=O>[ClH:2].[ClH:1].[CH:20]1([C:9]2[NH:8][C:7]3[C:6]4=[N:5][CH:4]([CH2:3][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:15][N:14]4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:10]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCN1C(=O)N2CC(CCl)N=C2c2[nH]c(C3CCCC3)nc21
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCN1C(=O)N2CC(CN3CCCCC3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 80 °C
Yield: 48.4 %

Procedure:
Compound 26 (49 mg, 0.14 mmol) obtained in Example 26 was dissolved in dimethyl sulfoxide (5 mL), to the solution was added piperidine (100 μL, 1.01 mmol, 7.2 equivalents), and the mixture was stirred with heating at 80° C. for 3.5 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5), to the product was added a 4 mol/L solution of hydrogen chloride in ethyl acetate, then the mixture was concentrated. The residue was crystallized from acetone to obtain the title compound (31 mg, 48%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[O:49][CH3:50]>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:43]([F:42])[CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: COc1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(C(=O)N(C)C)c2)cc1F

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3-fluoro-4-methoxyphenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:55])[C@@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([O:24][C:25](=[O:55])[C@@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=CC1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.0.093 g, 0.4 mmol), (2S)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]amino}butanedioic acid dibenzyl ester (0.4 mmol) and glacial acetic acid (0.022 g, 0.4 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.025 g, 0.4 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give the product (0.074 g).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([C:17]2[O:18][C:19]3[N:20]=[C:21]([O:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:22]=[C:23]([CH2:26][CH2:27][CH3:28])[C:24]=3[N:25]=2)[CH:14]=[C:13]([CH3:36])[C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[CH3:36][C:13]1[CH:14]=[C:15]([C:17]2[O:18][C:19]3[N:20]=[C:21]([O:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:22]=[C:23]([CH2:26][CH2:27][CH3:28])[C:24]=3[N:25]=2)[CH:16]=[C:2]([CH3:1])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCc1nc(OCCC(F)(F)F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(OCCC(F)(F)F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 103 %

Procedure:
Analogously to example 1 (j), the reaction of 12 mg of tert-butyl {2,6-dimethyl-4-[7-propyl-5-(3,3,3-trifluoropropoxy)oxazolo[5,4-d]pyrimidin-2-yl]phenoxy}acetate with trifluoroacetic acid gave 11 mg (83%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:9])[C:7]#[N:8])[C:3]#[N:4].[NH3:10]>>[NH2:4][C:3]1[C:2]([CH3:1])=[CH:5][C:6]([CH3:9])=[C:7]([NH2:10])[N:8]=1
Reactant: N
Reactant: CC(C#N)CC(C)C#N
Product: Cc1cc(C)c(N)nc1N
Temperature: 200 °C

Procedure:
3,5-dimethylglutarimidine is prepared from 2,4-dimethylglutaronitrile using the procedure of Example 2. One equivalent of 3,5-dimethyiglutarimidine is combined with Pd·C catalyst in a Hastelloy shaker tube to which liquid NH3 (59 eq.) is added. The mixture is heated at 200° C. for 45 h. The mixture is cooled to ambient temperature and the excess NH3 removed by N2 purge. The crude mixture is suspended in anhydrous MeOH, the catalyst is removed by syringe filtration, and the crude reaction mixture is concentrated in vacuo. 3,5-dimethylglutarimidine conversion is >90% to give 2,6-diamino-3,5-dimethylpyridine in at least 1% net yield.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[F:18][C:19](I)([F:21])[F:20].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:18][C:19]([F:21])([F:20])[C:16]1[C:14]([NH2:15])=[N:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: FC(F)(F)I
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
0.24 g (1.0 mmol) of cytidine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethylcytidine (19F-NMR yield: 24%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethylcytidine was obtained (0.034 g, yield: 11%) by column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH:24]=[CH2:25].Cl>CN(C=O)C>[CH2:22]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:2]([O:1][CH2:9][CH2:10][CH:2]=[CH2:3])[CH:3]=1)[CH2:23][CH:24]=[CH2:25]
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: C=CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCOC(=O)c1cc(OCCC=C)cc(C(F)(F)F)c1
Yield: 158.5 %

Procedure:
3-Hydroxy-5-trifluoromethyl-benzoic acid (2.17 g, 10.6 mmol), potassium carbonate (8.73 g, 63.2 mmol) and 4-bromo-1-butene (4.34 ml, 43.7 mmol) were dissolved in DMF (21 ml), and this mixture was irradiated in a microwave apparatus (100° C., 60 min). The reaction solution was poured into a cooled aqueous dilute hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give 3-but-3-enyloxy-5-trifluoromethyl-benzoic acid but-3-enyl ester (2.64 g, 80%).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:13].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>CCOC(C)=O>[CH3:6][C:7]1[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][N+:8]=1[O-:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc[n+]1[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A 25 mL round bottom flask was charged with conc. H2SO4 (1 mL) and cooled to 0° C. 2-Methylpyridine 1-oxide (0.4 g, 0.003 mol, Aldrich) was added in one portion, followed by the addition of fuming HNO3 (1 mL, spectrochem, india) in a drop-wise fashion. The reaction was stirred at rt for 30 min and a further 12 h at 70° C. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, EtOAc (10 mL) was added to the reaction mixture after cooling to 0° C. and the reaction was neutralized to pH-8-9 with 40% NaOH solution, and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J=5.4 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.92 (dd, J=1.8, 5.1 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[N:13][NH:12][C:11]=1[NH2:24].O.NN>C(O)C.[Ni]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[C:11]([NH2:24])[NH:12][N:13]=2)=[CH:20][CH:19]=1
Reactant: Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1-c1nc2ccccc2s1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2n[nH]c(N)c2-c2nc3ccccc3s2)cc1
Reaction time: 2 h
Yield: 24.9 %

Procedure:
An aqueous solution of Raney Ni (1 mL) was added to a suspension of 4-benzothiazol-2-yl-5-(4-nitrophenyl)-2H-pyrazol-3-ylamine (115 mg, 0.34 mmol) in ethanol (20 mL). To the vigorously stirring solution was added hydrazine hydrate dropwise in 3 portions (3×50 mg, 3 mmol in total), and the resulting mixture was then stirred for 2 hrs. The solids were removed by filtration and the mother liquor was evaporated to afford the crude material. The residue was purified by flash column chromatography eluting with CH2Cl2:MeOH=9:1 to yield 26 mg (25%) of the title compound as a cream coloured solid. MS (m/z, ES+): 308.1 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:19][O:20][C:21](=[O:39])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31]CC2C=CC=CC=2)=[CH:27][CH:26]=1)[NH2:23]>>[CH3:19][O:20][C:21](=[O:39])[CH:22]([NH:23][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7](=[O:8])[C:6]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)C2CCCCC2=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(OC)cc1
Yield: 28.5 %

Procedure:
The title compound (2.31 g) was prepared from 4.64 g (20 mmol) of 2-(4-methoxybenzoyl)-cyclohexanone (Howard, A. S. et. al. Tetrahedron Lett. 1979, (15), 1339-40) and 6.43 g (20 mmol) of O-benzyl-L-tyrosine methyl ester hydrochloride as a yellow solid as described for Intermediate 161: low resolution MS (Cl) m/e 406 (MH+).