Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:22]([O-])=O)[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8]#[N:9])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(O)C.Cl>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8]#[N:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)cc([N+](=O)[O-])c1Oc1ccccc1OC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(C#N)cc(N)c1Oc1ccccc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.59 g of 3-allyloxy-4-(2-methoxy-phenoxy)-5-nitro-benzonitrile were dissolved in ethanol (120 ml), a solution of tin dichloride dihydrate (8.55 g) in 37% HCl (25 ml) was added dropwise thereto at room temperature and the mixture was subsequently stirred at room temperature for 12 hours. The mixture was poured on to ice-water, adjusted to pH 7 and the product was extracted with ethyl acetate. After usual processing of the organic phase there was obtained 3-allyloxy-5-amino-4-(2-methoxy-phenoxy)-benzonitrile as a white solid.
Reaction SMILES: [NH2:1][CH2:2]C(O)=O.[OH-].[K+].[F:8][C:9]([F:25])([F:24])[C:10]([C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[Cl:23])=[CH:13]OC)=O.[CH2:26]([OH:28])[CH3:27]>>[C:26]([N:1]1[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[C:10]([C:9]([F:8])([F:24])[F:25])=[CH:2]1)(=[O:28])[CH3:27]
Reactant: CCO
Reactant: NCC(=O)O
Reactant: COC=C(C(=O)C(F)(F)F)c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Product: CC(=O)n1cc(-c2cccc(Cl)c2Cl)c(C(F)(F)F)c1
Temperature: 45 °C

Procedure:
2.7 g of glycine and 2.0 g of potassium hydroxide are dissolved in 160 ml of ethanol, and the mixture is heated to 45° C. There are then added at this temperature 9.9 g of the α-trifluoroacetyl-β-methoxy-2,3-dichlorostyrene produced according to Example P2, and the reaction mixture is refluxed for 90 minutes. The mixture is subsequently concentrated in vacuo; to the residue are afterwards added 150 ml of acetic anhydride, and the new mixture is heated at 100° C. for 45 minutes. After the evolution of CO2 has subsided, the solvent is removed by evaporation, and the residue is taken up in toluene, and filtered through SiO2. The filtrate is again concentrated by evaporation, and the oily residue is covered with hexane, in the course of which N-acetyl-4-(2,3-dichlorophenyl)-3-trifluoromethylpyrrole precipitates in the form of beige crystals, m.p. 65°-66° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](=[O:48])[NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol, Example 25: step c) was dissolved into THF (3 mL). To this was added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol) and the reaction was stirred at RT for 2 hours. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo resulted in the title compound that was used without further purification. ESI-MS (m/z): Calcd. for C31H37N3O7S3: 660.2 (M+1); found: 660.8.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O.[OH-].[Na+]>C(O)CC>[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:17]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1cncc(-c2ccnc(Nc3cccc(-n4ccnc4)c3)n2)c1
Yield: 67 %

Procedure:
Two and 73 hundredths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 1.76 grams of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, 25 ml of n-propanol and 2 equivalents (2 ml) of 10N NaOH at pH=11 is refluxed for twenty-four (24) hours. The products are isolated by quenching the reaction mixture including any precipitated solids into water followed by filtration. These filtered solids are re-suspended in water to remove inorganic salts, filtered and air dried to give 2.1 g (67% yield) of the desired product, mp 95°-120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6]CC(C)(C)N1.C([Li])CCC.[C:16]([C:20]1[N:21]=[C:22]([Cl:30])[C:23]2[N:24]([C:26](=[O:29])[NH:27][N:28]=2)[CH:25]=1)([CH3:19])([CH3:18])[CH3:17].C(=[O:35])C(C)C>C1COCC1>[C:16]([C:20]1[N:21]=[C:22]([Cl:30])[C:23]2[N:24]([C:26](=[O:29])[NH:27][N:28]=2)[C:25]=1[CH:6]([OH:35])[CH2:7][CH:2]([CH3:10])[CH3:1])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CC(C)C=O
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(C(C)(C)C)nc(Cl)c2n[nH]c(=O)n12
Temperature: -30 °C

Procedure:
A flame-dried flask was charged with THF (3.0 mL) and 423 mg of 2,2,6,6-tetramethylpiperidine. The solution was cooled to −30° C. and 1.0 mL of a 2.5 M solution of n-butyllithium in hexanes was added dropwise. The mixture was warmed to 0° C. for 20 min. and then cooled to −78° C. A solution of 226 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one in THF (2.0 mL) was added dropwise and the resulting solution was stirred for one h prior to the addition of 129 mg of isobutyraldehyde. The mixture was warmed to 0° C. and the reaction was quenched by the addition of sat. ammonium chloride solution followed by adjusting the pH of the solution to 3.0 with 2N HCl. The mixture was extracted with EtOAc and the organic layer was washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to provide 6-tert-butyl-8-chloro-5-(1-hydroxy-3-methyl-butyl)-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a white solid. MS (M+H+)=313.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
A mixture of methyl 4-[({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)methyl]benzoate (step 1, 154 mg, 0.37 mmol), tetrahydrofuran (2 mL), methanol (2 mL), and 2 N sodium hydroxide (2 mL) was stirred at room temperature for 4 h. The mixture was poured into 1N hydrochloric acid (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by TLC [dichloromethane/ethyl acetate (1:2)] to give 98 mg (66%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 9.13 (1H, t, J=6.0 Hz), 8.29 (1H, dd, J=2.6, 1.5 Hz), 8.22 (1H, dd, J=2.6, 1.5 Hz), 7.88 (2H, d, J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.29–7.26 (4H, m), 4.60 (2H, d, J=6.0 Hz); MS (ESI) m/z 401 (M+H)+, 399 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:2].C(OCC)(=O)C.[ClH:30]>>[ClH:30].[ClH:30].[CH2:22]([N:3]([CH2:1][CH3:2])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:23]
Reactant: CCN(CC)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc2c(c1)OCCNC2
Yield: 62.9 %

Procedure:
A solution of tert-butyl 8-(diethylamino)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (250 mg, 0.780 mmol) in 4N hydrogen chloride-ethyl acetate (6 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (144 mg, 62.9%) as a solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[CH3:22][C:16]1[CH:21]=[CH:20][C:19]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of AlCl3 (1.1 equivalents) in CH2Cl2 (40 ml) a solution of m-anisoylchloride (12.0 g) and toluene (1 equivalent) in CH2Cl2 (10 ml) is dropwise added. The resulting mixture is stirred at room temperature for 4 hours, then poured into 200 ml of a mixture ice-37% by weight HCl (1/1 v/v). The organic phase and the aqueous phase are separated. The organic phase is dehydrated with sodium sulphate. Filtration is then effected and the organic solvent evaporated. 4-methyl-3′-methoxybenzophenone is obtained. Yield: quantitative. IR (nujol) (λ=cm−1) 1690 (C═O); 1H-NMR (CDCl3) δ 2.44 (s, 3H); 3.86 (s, 3H); 7.08-7.18 (m, 1H); 7.20-7.40 (m, 5H); 7.73 (d, 2H, J=8.4 Hz). Anal. calc. for C15H14O2: C, 79.62; H, 6.24. Found: C, 79.53; H, 6.22.
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][CH3:5].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C:12](=[CH:14][CH:15]=[O:16])[CH3:13])[CH3:8].[NH4+].[Cl-]>O1CCCC1>[CH3:13][C:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:6])[CH3:8])=[CH:14][CH:15]([OH:16])[CH:3]=[CH:4][CH3:5]
Reactant: CC=CBr
Reactant: CC(C)=CCCC(C)=CC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CC(O)C=C(C)CCC=C(C)C
Reaction time: 8 h

Procedure:
12 g. of magnesium turnings were suspended under nitrogen in 250 ml. of dry tetrahydrofuran. Between 60° and 65°, 60 g. of 1-bromopropene dissolved in 50 ml. of tetrahydrofuran were added dropwise. During the addition, to prevent escaping of 1-bromopropene, the reflux condenser fitted on the reaction flask was cooled to -40°/-50°. When all Mg had reacted, the mixture was cooled to 20° and 76 g. of citral was added dropwise with cooling. After standing overnight, the mixture was poured into 1.5 liter of concentrated aqueous NH4Cl at 0°. The mixture was extracted 3 times with ether and the combined ether extracts treated as usual. After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene, b.p. 70°/0.1 Torr was obtained as a liquid with following constants : nD20 =1.4950; d420 =0.9145.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([NH:26][C:27](=[O:36])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([NH:26][C:27](=[O:36])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[N:16]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Sc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
The product from Example 103C (23 mg, 0.043 mmol) in CH2Cl2 (4 mL) was treated with TFA (1 mL). The reaction mixture was stirred at room temperature for 20 minutes, concentrated, and the resulting residue was purified by HPLC (conditions from Example 10C) to afford 9.3 mg (50%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.31 (dd, J=7.9, 0.9, 1H), 8.12 (d, J=7.8, 1H), 8.06-7.98 (m, 1H), 7.97-7.89 (m, 1H), 7.46-7.36 (m, 2H), 7.34-7.28 (m, 2H), 7.24-7.15 (m, 2H), 6.64-6.56 (m, 2H), 3.63 (s, 2H); MS (APCI+) M/Z 437 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:24])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])OC(C)(C)C)=[C:10]([OH:22])[C:9]=1[F:23])(=[O:3])[CH3:2].Cl.[C:26]([O:29][CH2:30][CH3:31])(=O)[CH3:27].C(O[CH2:36][CH3:37])(=O)C>>[C:1]([NH:4][C@@H:5]([CH3:24])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:12]2[CH:11]=[CH:10][C:26]([O:29][CH2:30][C:31]3[CH:37]=[CH:36][CH:24]=[CH:5][CH:6]=3)=[CH:27][N:13]=2)=[O:21])=[C:10]([OH:22])[C:9]=1[F:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C)COc1ncc(NC(=O)OC(C)(C)C)c(O)c1F
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ncc(NC(=O)c2ccc(OCc3ccccc3)cn2)c(O)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (6-(((2S)-2-acetamidopropyl)oxy)-5-fluoro-4-hydroxypyridin-3-yl)carbamate (453 mg), 4M hydrogen chloride/ethyl acetate (15 mL) and ethyl acetate (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Using the obtained residue and 5-(benzyloxy)pyridine-2-carboxylic acid, and in the same manner as in Step D of Example 83 and Step B of Example 123, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH3:35])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1000 mg) and paraformaldehyde (138 mg) in dichloromethane (20 ml) were added acetic acid (0.26 ml) and sodium cyanoborohydride (144 mg) in an ice bath. The mixture was stirred at room temperature overnight and then methanol (20 ml) was added. The resulting mixture was stirred at 30° C. for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (761 mg, yield 74%) as a yellow oil.
Reaction SMILES: [CH3:1][C@:2]([C:14]([NH:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].[CH:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH:28]1[O:37][C:38](Cl)=[O:39])[CH2:34]2>C1COCC1.C(OCC)(=O)C>[CH:29]12[CH2:35][CH:33]3[CH2:32][CH:31]([CH2:36][CH:27]([CH2:34]3)[CH:28]1[O:37][C:38](=[O:39])[NH:3][C:2]([CH2:4][C:5]1[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=1)([CH3:1])[C:14]([NH:16][CH:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:30]2.[C:38](=[O:39])([O-:15])[O-:37]
Reactant: C[C@@](N)(Cc1c[nH]c2ccccc12)C(=O)N[C@H](CO)Cc1ccccc1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NC(CO)Cc1ccccc1
Product: O=C([O-])[O-]
Yield: 20 %

Procedure:
A solution of the α-methyl-D-tryptophyl-L-phenylalaninol (0.5 g, 1.42 mmol) and 4-N,N-dimethylaminopyridine (0.2 g, 1.64 mmol), in anhydrous THF (20 mL) was treated dropwise with a solution of 2-adamantylchloroformate (1.4 mmol) in anhydrous THF (20 mL) at room temperature. The reaction was monitored by IR spectroscopy. Once complete, the reaction mixture was diluted with ethyl acetate and washed with 1M citric acid solution, then water. The dried (MgSO4) organic phase was evaporated to dryness and chromatographed over silica using 2% MeOH:98% CH2Cl2 as eluant. This gave the required compound (65% along with 20% carbonate impurity. NOTE: Some of the more acid labile urethanes required chromatography on neutral stationary phases. mp 96°-100° C. (EtOAc-hexane); IR (KBr) 3316, 1695 and 1658 cm-1 ; NMR (CD3OD) δ1.28 (3H, s), 1.55 (2H, m), 1.68-2.06 (12H, m), 2.76 (2H, ABx, J 13.5 and 17Hz), 3.31 (2H, Abq, J 14.5Hz), 3.45 (2H, m), 4.12 (1H, m), 4.78 (1H, br.s) and 6.8-7.5 (10H, m); Anal (C32H39N3O4), C, H, N.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:80][C:81]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:80][C:81]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:25]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1NC(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,6-dimethylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a yellow solid (22%).
Reaction SMILES: [F:1][CH:2]([CH2:12][O:13]C(=O)C)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].Cl>>[F:1][CH:2]([CH2:12][OH:13])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OCC(F)Cn1ccnc1[N+](=O)[O-]
Agent: Cl
Product: O=[N+]([O-])c1nccn1CC(F)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To 910 mg (3.94 mmol) of 1-(2'-fluoro-3'-acetoxypropyl)-2-nitroimidazole, 6N-HCl was added and stirred overnight at room temperature. The reaction mixture was concentrate and subjected to isolation and purification by silica gel column chromatography to give 280 mg of 1-(2'-fluoro-3'-hydroxypropyl)-2-nitroimidazole.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Na].[C:14](=[O:16])=[O:15]>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: [Na]
Solvent: Cc1ccccc1C
Product: Cc1cc(C(=O)O)c(O)c(C(C)(C)C)c1

Procedure:
One hundred and sixty four grams of 2-tertiarybutyl-4-methylphenol is dissolved in 500 ml. of xylene. 23 g. of dried metal sodium is added therein and dissolved. The resulting product is a suspension of white powder in xylene. The product is placed in a porcelain ball mill having a capacity of 1000 ml., and milled for about 3 hours. The product is placed in an autoclave having a capacity of 1000 ml. and carbon dioxide gas pressure of 20kg/cm2 is blown therein at about 150°C. to effect a reaction for about 5 hours. By same treatments thereof as in Examples 2 and 4, 3-tertiary butyl-5-methylsalicylic acid is produced.
Reaction SMILES: ClC1N2N=C(C)C=C2N=C(NC(=O)[C:14]2C=[CH:18][C:17]([C:20](O)(C)C)=[N:16][CH:15]=2)C=1.CN1C(=O)[CH2:29][CH2:28][CH2:27]1>>[CH:28]([N:16]([CH2:15][CH3:14])[CH:17]([CH3:18])[CH3:20])([CH3:29])[CH3:27]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)nc3)cc(Cl)n2n1
Reactant: CN1CCCC1=O
Product: CCN(C(C)C)C(C)C

Procedure:
In a 2 ml microwave vial was placed N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(2-hydroxypropan-2-yl)nicotinamide (11C, 75 mg, 0.217 mmol) and 1-(piperidin-4-yl)urea, HCl salt (39 mg, 0.22 mmol). To the sealed vial was then added NMP (1 ml) and then N,N-diisopropylethylamine (0.079 ml, 0.46 mmol) to give a deep blue solution. The mixture was then heated in the microwave at 100° C. for 10 minutes. After cooling to room temperature, the crude product mixture was purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled product (47 mg, 48% yield) as an off white powder. 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 9.07 (dd, J=2.4, 0.9 Hz, 1H), 8.38 (dd, J=8.3, 2.3 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.33 (s, 1H), 6.17 (d, J=0.5 Hz, 1H), 6.06-6.15 (m, 1H), 4.31 (d, J=12.6 Hz, 2H), 3.69 (br. s., 1H), 3.22 (t, J=10.9 Hz, 2H), 2.38 (s, 3H), 1.90-1.99 (m, 2H), 1.51 (br. s., 2H), 1.47 (s, 7H); ESI-MS: m/z 453.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li+].CC([N-]C(C)C)C.[CH2:19]([C:23]1[C:27]([CH2:28]Cl)=[C:26]([CH3:30])[O:25][N:24]=1)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([C:23]1[C:27]([CH2:28][CH2:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[C:26]([CH3:30])[O:25][N:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CCCCc1noc(C)c1CCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (157 mg, 1.0 mmol) in THF (3 mL) at −78° C. and under argon was added LDA (1.0 mL of a 2M solution in THF, 2.0 mmol) dropwise. After 1.5 h a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (188 mg, 1.0 mmol) in THF (2 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (1 N, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (210 mg, 68%) as an off white solid. MS: m/e=307.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:33])([F:32])[CH2:28][C:29]([OH:31])=[O:30]>>[F:26][C:27]([F:33])([F:32])[CH2:28][C:29]([O:31][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:30]
Reactant: O=C(O)CC(F)(F)F
Reactant: ON=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)CC(F)(F)F)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 3,3,3-trifluoropropanoate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and 3,3,3-trifluoropropionic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 3.94-4.17 (2H, m), 3.54-3.79 (2H, m), 3.37 (2H, q), 2.23-2.43 (2H, m), 1.65-1.96 (2H, m).