Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH:9]([OH:11])[CH2:8][CH2:7][C:6]1([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[OH:12])[CH3:3].[C:25]([Cl:30])(=[O:29])[CH2:26][CH2:27][CH3:28].O>C1COCC1>[ClH:30].[CH3:3][N:2]([CH2:4][CH:5]1[C:6]([OH:12])([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]=2)[CH2:7][CH2:8][CH:9]([O:11][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH2:10]1)[CH3:1]
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2cc(C3(O)CCC(O)CC3CN(C)C)ccc2c1
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)OC1CCC(O)(c2ccc3cc(OC)ccc3c2)C(CN(C)C)C1
Product: Cl
Reaction time: 0.33 h

Procedure:
70.0 g 2-dimethylaminomethyl-1-(6-methoxynaphthalen-2-yl)cyclohexane-1,4-diol were suspended in 560 ml THF p.a., 44.0 g potassium-tert.-butylate added in portions, the mixture stirred for 20 minutes, 21.0 ml butyryl chloride added dropwise, the mixture stirred for a further 20 minutes and a further 21.0 g potassium-tert.-butylate and 20.0 ml butyryl chloride respectively added again twice in accordance with the above model. For working up, 290 ml water were added with ice bath cooling, the phases separated, the mixture extracted once with ethyl acetate, the combined organic phases washed with 1 M sodium hydrogen carbonate solution, dried by magnesium sulphate, filtered and concentrated. 47.1 g of the hydrochloride of butyric acid 3-dimethylaminomethyl-4-hydroxy-4-(6-methoxynaphthalen-2-yl)cyclohexyl ester were obtained from the crude product obtained (90 g) in the same way as in AAV 1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].[H-].[Na+].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1>CS(C)=O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:13][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:3]
Reactant: Brc1nccs1
Reactant: CN(C)CCC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1nccs1)c1ccccc1

Procedure:
Following the method of Example 3, reaction of N,N-dimethyl-3-hydroxy-3-phenylpropylamine, sodium hydride and 2-bromothiazole in DMSO gives the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH2:4][C@H:3]1[OH:16].[Li][CH2:18]CCC.CI>C1COCC1>[CH3:18][C@H:4]1[CH:5]=[C:6]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][C@H:2]([CH3:1])[C@@H:3]1[OH:16]
Reactant: [Li]CCCC
Reactant: C[C@H]1C=CC(Sc2ccccc2)=CC[C@H]1O
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C=CC(Sc2ccccc2)=C[C@H](C)[C@H]1O
Temperature: -100 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A solution of alcohol 29 (887 mg, 3.82 mmol) in THF (50 mL) was cooled to −78° C., and 3.20 mL of n-BuLi (2.5 M in hexanes, 8.00 mmol) was added dropwise. The mixture was slowly brought to −7° C. over 1 h, and stirred at this temperature for 10 min. It was then cooled to −100° C. in a THF-liquid N2 bath. To this cold dark orange solution was slowly added a solution of MeI (0.72 mL, 11.56 mmol) in THF (5 mL) over 30 min via syringe pump. The resulting light yellow solution was warmed to −60° C. prior to quenching with saturated aqueous NH4Cl. After warming to room temperature, the two layers were separated, and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, and dried over Na2SO4. Flash column chromatography (EtOAc/hexanes; 1:4) afforded 660 mg (70% yield) of 31 as a white solid. mp 81.5-83.5° C.; [α]20D=+407.8 (c=0.55CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.20-7.35 (m, 5H), 6.27 (d, J=5.4 Hz, 1H), 5.98 (br d, J=10.8 Hz, 1H), 5.75 (dd, J=4.5 Hz, 10.8 Hz), 3.79 (dd, J=2.7 Hz, 6.0 Hz, 1H), 2.55 (m, 1H), 2.45 (m, 1H), 1.65 (br s, 1H), 1.25 (d, J=7.5 Hz, 3H), 1.20 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 140.9, 138.7, 136.1, 130.5, 130.2, 129.9, 129.2, 126.7, 84.7, 43.5, 38.1, 19.4, 17.6; Analytical. Calculated for C15H18OS: C, 73.13; H, 7.36. Found: C, 72.42; H, 7.22.
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C=CCCCC>C1(C)C=CC=CC=1>[CH3:10][C:9](=[O:11])[CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Product: CCCCCCC(C)=O

Procedure:
Under the same reaction procedure and conditions as in Example 2 (tristriphenylphosphine rhodium (I) chloride 10 mol %, 2-amino-3-pycoline 20 mol %, 150° C., 48 hours), benzyl acetone 32 mg (0.22 mmol) was reacted with various amounts of 1-hexene in toluene 100 mg. A measurement was made of the yields of 2-octanone and the results are given in Table 6, below.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].[C:19]([O-])([O-])=O.[K+].[K+].CI.O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[CH:17]=[O:18])=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2c(C=O)cnn2C)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (624 mg, 4.5 mmol) in acetonitrile (6 ml) was stirred at 0-5° C. for 1 h. Methyl iodide (310 mg, 2.2 mmol) was added and stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL), extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried, and concentrated under vacuum. The residue was purified by prep-TLC using Hexane:EtOAc (21:9) as eluent to afford 5-(4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (88 mg, Yield 21%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 1H), 8.05 (s, 1H), 7.36-7.32 (m, 2H), 7.06-7.02 (m, 2H), 4.69-4.64 (m, 1H), 3.84 (s, 3H), 1.0 (d, J=6 Hz, 6H) ppm. LCMS (method C): RT=2.11 min, m/z=245.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10](I)[C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nn(C3CCCCO3)c3nc(Cl)ccc23)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), and cesium carbonate (540 mg, 1.6 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 80° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M+H)+=318.0.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 68.8 %

Procedure:
First, 10.16 g (145 mmol) of crotonaldehyde and 10.09 g (60.4 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) were added as the solvent, and the mixture was heated under reflux for 15 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried in vacuo for 2 hours to give 9.11 g of 2-benzenesulfonyl-pyridine as colorless crystals (purity of 90%, yield of 62% based on benzenesulfonyl cyanide).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:12]=C(O)[C:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[C:9](O)[N:8]=1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C(C)C)(C)C.Cl[CH2:39][Cl:40]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:26][C:9]1[C:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[C:39]([Cl:40])[N:12]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2Cl)c(F)c1

Procedure:
According to scheme 1, step c, to a mixture of 2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine-4,6-diol 4 in an aprotic solvent preferably toluene (g/ml) preferably 5–15 parts, more preferably in 5–10 parts, most preferable in 7 parts, is slowly added at about 10–15° C., phosphorus oxychloride. Following complete addition of the phosphorus oxychloride, N,N-diisopropylethyl amine in a molar ratio of about 1:1 to 1:5, preferably in the range of 1:4 is slowly added at about 10–15° C. and the mixture heated to reflux for about 6 to 24 h, preferably about 6 h. The volatiles are removed by distillation to a residue which is further distilled with toluene preferably two times to afford a further residue. The further residue is dissolved in a solvent selected from ethyl acetate, dichloromethane and toluene, preferably ethyl acetate then partitioned by pouring into water while maintaining the temperature between about 5–15° C. The solvent layer is separated, washed with water, dried over sodium sulfate and filtered through a pad of filter aid such as diatomaceous earth or through hydrous magnesium silicate and most of the volatiles removed to a residue to which is added heptane forming a precipitated product. The precipitated product 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is collected and having a purity of >95% as shown by high pressure liquid chromatography (HPLC). Further, the 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is formed and isolated without chromatography.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6]1)[CH3:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>C1COCC1.O.C(OCC)(=O)C>[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[C:7](=[O:11])[CH2:6]1)[CH3:4]
Reactant: Fc1cccc(CBr)c1
Reactant: CCN1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1CCN(Cc2cccc(F)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Sodium hydride (60% oil dispersion, 0.176 g) was added to a stirred solution of 4-ethyl-piperazin-2-one (Intermediate 176, 0.512 g) in anhydrous THF (10 mL) and the mixture was stirred at room temperature for 10 minutes. 3-Fluorobenzyl bromide (0.827 g) was added and stirring was continued for 2 hours. The solution was diluted with water and ethyl acetate and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-5% to give 4-ethyl-1-(3-fluorobenzyl)piperazin-2-one (0.595 g) as a colourless oil.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([O:39]C)[CH:38]=1)[O:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([CH3:35])([CH3:34])[CH2:16][CH2:17][C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH2:21])=[O:20])[CH2:11]1>ClCCl>[NH3:12].[F:5][C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([OH:39])[CH:38]=1)[O:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([CH3:34])([CH3:35])[CH2:16][CH2:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:19]([NH2:21])=[O:20])[CH2:11]1
Reactant: COc1cc(F)cc(O[C@@H]2CCN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@@H](Oc2cc(O)cc(F)c2)C1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Boron tribromide (1M in dichloromethane, 1.2 mL, 1.224 mmol) was added to an ice-cooled solution of the product of example 73 (150 mg, 0.306 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with 0.88 ammonia solution and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 8 by dropwise addition of 2N hydrochloric acid (aq) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, afforded the title compound as a pale brown foam in 49% yield, 71 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1.C(O)(=O)C>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: Cc1cccnc1C1=CC(C)(C)Oc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccnc1C1CC(C)(C)Oc2ccccc21
Yield: 46.8 %

Procedure:
2.97 g of 2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1benzopyran were dissolved in 50 ml of ethanol and shaken at room temperature under a hydrogen atmosphere with 10% palladium-on-charcoal in the presence of 0.5 ml of acetic acid. After 24 hours the catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 1.4 g of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl) -2H-1-benzopyran together with mixed fractions containing this compound and starting material. The procedure described above was carried out on the mixed fractions to give 675 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl) -2H-1-benzopyran which was recrystallized from t-butyl methyl ether and then melted at 100-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([O:29]C)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([OH:29])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol), LiOH.H2O (69 mg, 1.16 mmol), H2O (2 mL) and methanol (20 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated HCl solution. The precipitate was collected by filtration to give the title compound as a white solid (57 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(C2C=C(F)[CH:24]=[CH:23][C:22]=2[C:28]([C:30]2[CH:35]=[CH:34][C:33](F)=[CH:32][C:31]=2C2CC2)=[O:29])CC1.C(=O)([O-])[O-].[K+].[K+].[ClH:46]>CS(C)=O.CO.C(OCC)C>[ClH:46].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([CH:22]4[CH2:23][CH2:24]4)=[O:29])=[CH:35][CH:34]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(F)cc1C1CC1)c1ccc(F)cc1C1CC1
Reactant: CC(C)N1CCN(C(=O)C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOCC
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)C4CC4)cc3)CC2)CC1
Temperature: 140 °C

Procedure:
To 1-isopropyl-4-(piperidine-4-carbonyl)-piperazine (D1)(0.25 g) and cyclopropyl-4-fluorophenyl ketone (0.3 g), dissolved in DMSO (5 ml) was added potassium carbonate (0.37 g). The reaction was heated to 140° C. for 2 h. After cooling the mixture, the inorganics were filtered off. The filtrate was diluted with MeOH (20 ml) and then poured onto a 10 g isolute SCX column which was washed with MeOH (50 ml). The product was eluted with 10% ammonia in MeOH (50 ml), and then further purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base which was dissolved in MeOH (4 ml) and treated with 1N HCl in diethyl ether (2 ml) to give the title compound (E105) as a solid (51mg). 1H NMR δ [DMSO-d6]: 0.93 (4H, m) 1.27 (6H, d, J=6.4 Hz), 1.5-1.8 (2H, m), 2.77-3.14 (7H, m), 3.38-3.48 (2H, m), 3.92-4.56 (4H, m), 6.98 (2H, d, J=9.2 Hz), 7.89 (2H, d, J=9.2 Hz), 10.6 (1H, br s). MS electrospray; (+ve ion) 384 (MH+).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].CO.C[O-].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](OC)=O)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[NH:5][N:6]=[C:7]([NH2:9])[N:8]=2)=[CH:19][CH:18]=1
Reactant: N=C(N)NN
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CO
Product: COc1ccc(Cc2nc(N)n[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a stirred mixture of N-aminoguanidine nitrate (5.50 g, 40 mmol) and anhydrous methanol (50 mL) cooled to 0 C was added sodium methoxide solution (25% in methanol, 9.2 mL, 40 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min before methyl 2-(4-methoxyphenyl)acetate (1.6 mL, 10 mmol) was added. The mixture was then stirred at 0° C. for 10 min, RT for 10 min, and 75° C. for 27 hr. The reaction mixture was cooled and diluted with 20 mL of water. Methanol was removed under vacuum and the aqueous solution was acidified to pH=3-4 with 3 N aqueous HCl solution. The solid obtained was filtered, washed with water, and recrystalized in ethanol-water to give 1.65 g (81% yield) of 5-(4-methoxybenzyl)-1H-1,2,4-triazol-3-amine as a white solid. (M+H)+=205.22
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:42]2[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH2:44][CH2:43]2)=[CH:8][C:9]=1[N:10]([CH:20]([CH2:33][O:34][SiH](C(C)C)C(C)C)[CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:42]2[CH2:43][CH2:44][C:45]([CH3:48])([CH3:49])[CH2:46][CH2:47]2)=[CH:8][C:9]=1[N:10]([CH:20]([CH2:33][OH:34])[CH2:21][OH:22])[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO[SiH](C(C)C)C(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-[(1-diisopropylsilanyloxymethyl-2-triisopropylsilanyloxy-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (60 mg, 0.078 mmol) in THF (1 mL) was treated with HF.pyridine (0.1 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and added to solid NaHCO3. It was stirred at room temperature for 2 h, filtered and evaporated. Pure 5-(4,4-dimethyl-cyclohexyl)-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained on chromatography over silica gel (EtOAc as eluent) (32 mg, 89%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.OCC1[CH:21]=[CH:20][C:19]([SiH:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.CO>C(OCC)(=O)C>[C:5]([O:4][CH2:1][C:2]1[CH:17]=[CH:18][C:19]([SiH:22]([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:27])[CH3:28])=[CH:20][CH:21]=1)(=[O:7])[CH3:6]
Reactant: CC(C)[SiH](c1ccc(CO)cc1)C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc([SiH](C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Acetic anhydride (3.1 mL, 33 mmol) and 4-N,N-dimethylaminoprydine (7.3 mg, 6 mmol) were added under argon atmosphere to pyridine (100 mL) dissolving 4-(hydroxymethyl)phenyl-diisopropylsilane (3) (4.9 g, 22 mmol). The resulting mixture was then stirred for 2 hours at a room temperature and methanol (20 mL) was added to it. The reaction mixture was diluted with ethyl acetate (400 mL), and then extracted three times with saturated saline solution (300 mL). An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure to give a desired product (5.4 g, 93%). Its NMR data are as follows:
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:67])[CH:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:66][CH:63]5[CH2:64][CH2:65][CH:60]([N:59]([CH3:67])[CH3:58])[CH2:61][CH2:62]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCC(N(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N1,N1-dimethylcyclohexane 1,4-diamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.96 (m, 18H) 2.17 (s, 6H) 3.31 (s, 3H) 3.73 (m, 1H) 3.92 9m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.46 (m, 1H) 7.42-7.59 (m, 2H) 7.89 (s, 1H) 8.11 (m, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). Melting point: 208-214° C. [M+H] calculated for C30H41F2N7O3, 586. found 586.