Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1.[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Agent: O=S(=O)(O)O
Product: O=C1C2=NCCCN2c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a cold mixture of 7-chloro-3,4-dihydropyrimido[1,2-a]indole-10(2H)-one (0.221 g, 1.00 mmol ) in concentrated H2SO4 (1 mL), was added fuming nitric acid (0.042 mL, 1.00 mmol ) drop-wise with cooling in a ice/brine bath (−10° C.). After stirring for 10 minutes the ice bath was removed and stirring continued for 1 hour at room temperature. Controlling the temperature with an ice bath, fresh fuming HNO3 (0.021 mL) was added. After stirring for an additional hour the mixture was added to ice and basified with concentrated NH4OH. The resulting yellow solid was filtered, dissolved in CH2Cl2 and filtered again. The filtrate was washed with H2O and the organic layer was separated and concentrated to give the title compound as a bright yellow solid (0.209 g, 79% yield). Anal. Calc'd for C11H8ClN3O3+0.2H2O: C, 47.60; H, 3.00; N, 14.87. Found: C, 47.58; H, 3.02; N, 14.85. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 266 [M+H] one chlorine pattern observed. m.p.: 152-165° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([CH:15](O)[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:6]=1[CH:22]([CH3:24])[CH3:23])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]2[O:14][C:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][C:7]=2[C:6]=1[CH:22]([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCC(CC)C(O)c1c(O)cc(C(C)C)c(OC(C)=O)c1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(CC)Cc2c(cc(C(C)C)c(OC(C)=O)c2C(C)C)O1
Yield: 89.7 %

Procedure:
0.51 g of 4-acetoxy-2-(2-ethyl-1-hydroxybutyl)-3,5-diisopropylphenol dissolved in 10 ml of toluene, 0.58 g of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was combined with a 2N aqueous sodium hydroxide solution and extracted with hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 433 mg of 5-acetoxy-2,2-diethyl-4,6-diisopropyl-2,3-dihydrobenzofuran as a yellow oil (yield 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:25])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[C:27]1[CH:28]=[CH:29][C:30](=[O:35])[N:31]([CH2:33][CH3:34])[CH:32]=1>>[CH2:23]([C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:25])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][C:30](=[O:35])[N:31]([CH2:33][CH3:34])[CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1)[CH3:24]
Reactant: CCn1cc(Br)ccc1=O
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O
Product: CC[C@@H](c1ccc(-c2ccc(=O)n(CC)c2)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 32 Method 2 Steps 3 and 4 using 5-bromo-1-ethylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.68 min, m/z=445 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([NH2:8])([CH3:7])[CH2:5][SH:6].[Cl:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1>C1C=CC=CC=1>[NH2:8][C:4]([CH3:7])([CH3:3])[CH2:5][S:6][C:13]1[N:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(N)CS
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(N)CSc1ccc(Cl)nn1
Yield: 36.4 %

Procedure:
To a suspension of 1.32 g of 61% sodium hydride in 20 ml of benzene was added dropwise at room tmperature a solution of 2.6 g of 2-methyl-2-aminopropanethiol in 10 ml of benzene. Then, a solution of 4.1 g of 3,6-dichloropyridazine in 10 ml of benzene was added, and the mixture was refluxed for 6 hours. After cooling, the reaction mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated to give 1.96 g of 3-(2-amino-2-methylpropylthio)-6-chloropyridazine.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].O.[CH3:14][N:15]=[C:16]=[O:17].[Cl-].[Na+]>C(O)(=O)C>[CH3:14][NH:15][C:16]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Reactant: CN=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)NC(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.1 mole of α-amino-4-hydroxybenzeneacetic acid dissolved in 500 ml of water containing 0.05 mole of acetic acid is added 0.11 mole of methyl isocyanate. This mixture is stirred for 30 minutes at room temperature. The reaction mixture is saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate is washed with water, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]=[O:13]>N1C=CC=CC=1>[OH:13][CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: C=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: c1ccncc1
Product: CC1(C)CC(O)CC(C)(C)N1CO
Temperature: 25 °C

Procedure:
In a 1-liter stainless steel container are placed 79 grams of 2, 2, 6, 6-tetramethyl-4-hydroxypiperidine, 132 grams of paraformaldehyde and 300 milliliters of pyridine. The flask is evacuated, filled with nitrogen and this process repeated 3 times. The flask is then sealed and heated at 135° to 140°C. for 30 minutes with rocking. The flask is then cooled quickly to room temperature, the contents removed and the mixture filtered. The pyridine is removed from the filtrate on a rotary evaporator. The remaining viscous oil is dissolved in ether, treated with activated charcoal, brought to a boil and filtered. The ether is removed from the filtrate on a rotary evaporator to yield 1-hydroxymethyl-2, 2, 6, 6 -tetramethyl-4-hydroxypiperidine as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:29])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=1)[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC.Br[Si](C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[Cl:29][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([Cl:1])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:26]([CH3:27])[CH3:28])[CH:19]=1)[CH2:5][P:6](=[O:7])([OH:10])[OH:13]
Reactant: CCOP(=O)(Cc1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1)OCC
Agent: BrB(Br)Br
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CP(=O)(O)O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a solution of diethyl 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzylphosphonate (0.59 g, 1.28 mmol) in CH2Cl2 (10.0 mL) at −30° C. was added bromotrimethylsilane (2.53 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (25.0 mL), cooled to −78° C. and to it was added BBr3 (19.0 mL, 19.0 mmol, 1.0 M solution in CH2Cl2). The reaction mixture was stirred at −78° C. for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into ice, concentrated and extracted with ethyl acetate. The organic layer was washed with water (20 mL×2), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford 3,5-dichloro-4-(3′-iso-propyl-4′-hydroxyphenoxy)benzylphosphonic acid as a brown solid (0.20 g, 40%): mp: 178-181° C.; LC-MS m/z=391 [C16H17Cl2O5P−H]−; 1H NMR (300 MHz, DMSO-d6): δ 9.08 (s, 1 H), 7.48 (s, 2 H), 6.72 (m, 2 H), 6.25 (m, 1 H), 3.18 (m, 1 H), 3.00 (d, J=21.0 Hz, 2 H), 3.11 (m, 1 H), 1.14 (d, J=6.0 Hz, 6 H); Anal. Calcd for (C16H17Cl2O5P+0.2 C4H8O2+0.5H2O): C, 48.30; H, 4.73. Found: C, 48.69, H, 5.16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].I[CH2:13][CH3:14]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH3:14])=[CH:4][C:3]=1[Cl:9]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)c(Cl)c1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
The 4-Bromo-3-chloro-phenol (24 mmol, 5 g) in anhydrous THF (50 mL) was added to a stirred solution of NaH (60% in mineral oil, 120 mmol, 4.8 g) in THF (100 mL) and DMF (42 mL) under N2 at room temperature. This solution stirred for 30 minutes. The iodoethane (240 mmol, 19.2 mL) was then added. The solution was stirred and was refluxed overnight. The reaction was cooled and quenched with 1 N HCl (150 mL), extracted into CH2Cl2 (2×150 mL), dried over MgSO4, concentrated in vacuo, and distilled under vacuum yielding 1-bromo-2-chloro-4-ethoxybenzene as a brown oil (4.59 g, 81%). 1H NMR (CDCl3, 300 MHz): δ7.42 (1H, d, J 8.7 Hz), 6.96 (1H, d, J 2.9 Hz), 6.64 (1H, dd, J 8.8 and 2.5 Hz), 3.95 (2H, q, J 7.0 Hz), 1.39 (3H, t, J 7.0 Hz.)
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Add ethyl 1-aminocyclopropanecarboxylate (89.2 g, 0.54 mol) to diisopropylethylamine (187.86 mL, 1.08 mol) in dichloromethane (900 mL) Immerse the flask in a cold water bath and slowly add 4-chlorobenzoic acid chloride (75.46 mL, 0.59 moles). After addition is complete, remove the bath, allow the reaction to equilibrate to 20° C., and stir for approximately 2 hours. Wash with 1N hydrochloric acid (HCl), followed by saturated sodium bicarbonate (NaHCO3), water, and then brine. Dry the organic layer over sodium sulfate (Na2SO4), filter, and concentrate under reduced pressure. Slurry the residue with heptane, filter, and rinse with heptane to give the title compound (142 g, 98%) as a white powder: MS (m/z): 268 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: O=C(O)C1Cc2cscc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cscc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene (3.95 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.5 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: COc1ccc(I)nc1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Product: COc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Yield: 33.9 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.214 g, 0.64 mmole) with 2-iodo-5-methoxypyridine (0.152 g, 0.64 mmole) using tereakis (triphenylphosphine)palladium(0) (30 mg) as catalyst in a manner as previously described for example 39b to give a yellow solid (0.060 g, 34%). 1H NMR (300 MHz, CDCl3) δ8.55 (1H, d, J=5.1 Hz), 8.43 (1H, s), 8.28 (1H, dd, J=1.3, 4.6 Hz), 7.34 (1H, m), 7.28 (1H, m), 7.24 (1H, d, J=5.8 Hz), 4.04 (3H, s).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:14]3[CH:15]4[CH2:18][CH2:19][N:11]([CH2:12][C:13]=3[C:5]=2[CH:4]=1)[CH2:17][CH2:16]4
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Product: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1

Procedure:
4-Bromophenylhydrazine hydrochloride (4.33 g, 19.37 mmol; Aldrich) and the product of Example 1A (2.70 g, 19.37 mmol) were processed as described in Example 1B to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.14-2.36 (m, 4 H), 3.17-3.25 (m, 1 H), 3.33-3.45 (m, 2 H), 3.45-3.65 (m, 2 H), 4.54 (s, 2 H), 7.18 (dd, J=8.8, 1.8 Hz, 1 H), 7.24 (d, J=9.1 Hz, 1 H), 7.51 (d, J=2.4 Hz, 1 H); MS (DCI) m/z 291/293 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]([C@H:9]([OH:18])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>ClCCl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH3:8])[C@H:9]([O:18][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
To a solution of (2S,3R)-2-(4-bromophenoxy)-5-pyridin-3-ylpentan-3-ol (2.01 g, Example 15d)) in dry dichloromethane (50 ml) was added tert-butyldimethylsilyl chloride (1.81 g) and imidazole (0.814 g) and the resulting solution stirred for 24 hours, concentrated and the residue purified by column chromatography on silica gel eluting with dichloromethane:diethyl ether (1:1) to afford the sub-title compound as an oil (2.52 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([Si](C)(C)C)[C:5]1=[O:13].[Li+].[CH3:16][CH:17]([N-]C(C)C)[CH3:18].C(Br)C=C>C1COCC1>[CH3:1][CH:2]([CH3:14])[CH2:3][C:4]1([C:17]([CH3:18])=[CH2:16])[CH2:8][CH2:7][NH:6][C:5]1=[O:13]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC1CCN([Si](C)(C)C)C1=O
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=C(C)C1(CC(C)C)CCNC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 3-(2-methylpropyl)-1-trimethylsilyl-2-pyrrolidinone (10.2 g, 47.8 mmol) and THF (153 mL) is cooled to -78° C., and LDA (2.0 M, 26.3 mL, 52.6 mmol) is added. The solution is stirred at -78° C. for 30 minutes and then allyl bromide (5.0 mL, 57 mmol) is added. The solution is allowed to warm to 5° C. over 2.5 hours, and is then stirred at 5° C. for 1 hour. After quenching with saturated aqueous ammonium chloride (25 mL), aqueous workup (EtOAc, MgSO4) and purification by column chromatography (1:9:10 v/v CH2Cl2 :EtOAc:hexane) provides 7.76 g (90%) of the title compound as an oil.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][N:29]1C(OC(C)(C)C)=O)=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[ClH:48]>O1CCOCC1.C(OCC)C>[ClH:48].[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)N1CCCN1C(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)N1CCCN1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.267 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[(2-tert.butyloxycarbonyl-1-pyrazolidinyl)carbonyl]valerohydrazide was treated with 2 ml of 4M hydrogen chloride in dioxan and stirred for 2 hours at room temperature. The mixture was diluted with diethyl ether and the resulting solid was filtered off, washed with diethyl ether and dried to give 0.142 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[(1-pyrazolidinyl)carbonyl]valerohydrazide hydrochloride in the form of a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(N1CCCC1C(O)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:13]2[NH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH2:10][CH:11]2[CH:12]1[CH2:25]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Product: CC(C)(C)OC(=O)N1C(c2ncc(-c3ccc(Br)cc3)[nH]2)CC2CC21
Yield: 60 %

Procedure:
3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.16 g, 60%) was prepared following the procedure for 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, substituting 2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI+: calc'd for C19H22BrN3O2: 403.09 (M+); Found: 404.76 (M+H+).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][C:9](=[O:12])[CH2:10][OH:11]>Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][C:9](=[O:12])[CH2:10][O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: C1=COCCC1
Reactant: O=C(CO)CO
Agent: Cl
Product: O=C(COC1CCCCO1)COC1CCCCO1
Temperature: 85 °C
Yield: 66.8 %

Procedure:
A mixture of 236.3 g 3,4-dihydropyran and 90.1 g 1,3-dihydroxy-2-propanone, to which had been added 20 drops of concentrated hydrochloric acid, was heated to 85° C at which temperature, an exothermic reaction began. A cooling bath was applied to maintain the temperature in the range 85°-95° C during the next 15 minutes when heat was again applied to maintain the temperature at 85°-95° C for 2 hours. Excess dihydropyran was removed by warming under reduced pressure and the residue was dissolved in 600 ml of diethyl ether. The ether solution was washed (4 × 200 ml) with 5% aqueous sodium carbonate, then with water (3 × 300 ml) and dried over magnesium sulfate. The dried solution was distilled under reduced pressure to give 172.7 g of 1,3-bis(2-tetrahydropyranyloxy)-2-propanone, b.p. 90°-97°/2 × 10-4 mm.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>>[CH3:24][C:22]1[N:23]=[C:19]([NH:18][C:3]([C:5]2[C:10]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[S:20][CH:21]=1
Reactant: COC(=O)c1nccnc1Nc1cncnc1
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2nccnc2Nc2cncnc2)n1

Procedure:
The title compound, MS: m/e=314.0 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid methyl ester and 2-amino-4-methylthiazole.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:21]([O:20][CH2:19][CH2:18][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(CCO[Si](C)(C)C(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxoazepan-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% ethyl acetate/hexanes, to provide compound (2f) in 48% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:28](=[O:30])=[O:29]>C(OCC)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:28]([OH:30])=[O:29])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Pyridin-3-yl-carbamic acid tert-butyl ester (6.20 g) was dissolved in anhydrous diethyl ether (260 mL), cooled to −78° C. and N,N,N′,N′-tetramethylethylendiamine (14.4 mL) was added. A solution of n-butyl lithium (1.6 M in hexane, 60 mL) was added slowly over a time period of 10 minutes. After the addition of the reagent was completed, the reaction mixture was allowed to warm to −10° C. and stirred at this temperature for 2 hours. The reaction mixture was then re-cooled to −78° C. and slowly poured on a stirred mixture of dry ice in diethyl ether. After stirring for 30 minutes, water was added to the reaction mixture and the layers were separated after complete dissolution of solid materials. The aqueous layer was washed 2× with diethyl ether and the pH-value of the aqueous layer was adjusted to 5-6. The organic layer was extracted 2× with MTB-ether. The combined organic layer was washed with a small amount of brine, dried over MgSO4 and concentrated in vacuum. The residue was washed with hexane to remove oily by-products and dried in vacuum to afford 1.19 g of the title compound as beige solid. The aqueous washing was concentrated on a rotary evaporator to approx. 50 mL, inorganic salts were filtered off and MTB-ether was added to the mother liquor. 6N hydrochloric acid was slowly added into the well-stirred mixture until the pH-value was adjusted to −3. The layers were separated, the aqueous layer was washed 2× with MTB-ether and 2× with chloroform. The combined organic layer was dried over MgSO4 and dried in vacuum to give another 2.03 g of beige solid. Together, the first organic extract and 3.22 g of the title compound of the formula