Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>O1CCCC1>[F:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of tetrahydrofuran (hereafter referred to as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.4 g of 1-chloro-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 5.8 g (yield 80%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-n-propyl-1-silacyclohexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([C:18](OCC)=[O:19])[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1>O1CCCC1>[CH3:7][C:8]1([CH2:18][OH:19])[CH2:17][CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 500 ml, round-bottomed flask was lithium aluminum hydride (1.772 g) in tetrahydrofuran (234 mL) to give a suspension. This suspension was cooled to 0° C. and ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (10.66 g) was added via addition funnel. The reaction was stirred overnight at room temperature and then cooled back down to 0° C. The excess lithium aluminum hydride was slowly quenched with 1.8 mL water, 1.8 mL aqueous NaOH (5N) and 5.6 mL water. The suspension was stirred until the salts turned white and was then filtered through a plug of silica gel. The filtrate was concentrated by rotary evaporation and the residue was purified by regular phase flash column chromatography (Analogix, 0-75% hexanes/ethyl acetate).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH3:7].CS(C)=O.O.Cl.[CH3:34][CH2:35]OCC>>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][C:34]#[CH:35])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC(CCCl)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: C#CCCC(CCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of 32.2 g. (85 moles) of 1-chloro-3-triphenylmethoxyhexane (Example 906) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25°-30° C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product is then purified by column chromatography of the residue on Florisil.
Reaction SMILES: [Cl-].[C:2]1([CH:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][N+:10]2[NH:11][CH:12]=[N:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[C:2]1([CH:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCC(C[n+]1cnc[nH]1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCC(Cn1cncn1)c1ccccc1
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To 11.7 g of the crude hydrochloride salt from Example 10 above in 200 ml of water is added 4.0 g (0.05 mole) of 50% sodium hydroxide. The mixture is stirred for 15 minutes and then the organic soluble material is extracted into 2×200 ml of ether. The combined extracts are washed with 2×50 ml of water, dried over anhydrous magnesium sulfate, and concentrated to give 8.3 g (78.5%) of the oil product.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C@@H:5]([CH2:15][O:16]C2CCCCO2)[CH2:4][S:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CCO>[OH:16][CH2:15][C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCCCCCCN1C(=O)SC[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 4-1 (0.97 g, 3.0 mmol) in 10 mL EtOH was added p-toluene sulfonic acid (50 mg) and the resulting solution was stirred overnight at room temperature. Triethylamine (0.1 mL) was added and the solution was concentrated in vacuo. The compound was purified by flash chromatography using 50–80% EtOAc/hexanes to yield 0.65 g of 4-2 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.92–3.73 (m, 3H), 3.68–3.60 (m, 1H), 3.42 (dd, 1H), 3.28 (dd, 1H), 3.10 (m, 1H), 2.37(t, 2H), 1.71–1.46 (m, 6H), 1.39–1.33 (m, 2H); MS (+ESI): m/z 243.1 (M+1)+.
Reaction SMILES: CC([O-])(C)C.[Na+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:18][CH:19]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-n2ccc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 36 h
Yield: 76.7 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (11.5 mg, 0.013 mmol, 5 mol % Pd), 2 [Example 1] (14.8 mg, 0.038 mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and indole (60 mg, 0.51 mmol). The tube was purged with argon then toluene (0.5 mL) and 1-bromo-4-fluorobenzene (55 μL, 0.50 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at 100° C. for 36 h The reaction was then diluted with ether (20 mL), filtered through celite and concentrated in vacua. The crude material was purified by flash chromatography on silica gel to afford 81 mg (77%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17]C)=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:15](=[O:17])[CH2:14][CH2:13][C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)=[CH:29][CH:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)CCc1ccc(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CNC(=O)CCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Yield: 58 %

Procedure:
The compound 26-2 (30 mg) prepared in Step 2 was dissolved in toluene (4 ml) and to the solution was added 4-t-butylbenzylamine (150 μl), followed by refluxing for 3 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was chromatographed on silica gel column (ethyl acetate/hexane=1/1) to yield the compound 26-3 (28 mg, 58%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N(c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)N(c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1)C1CCCCC1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)-cyclohexylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:41][C:40]3[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (230 mg, 0.494 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (75.6 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (34.5 mg, mp =105° C.). 1H NMR (360 MHz, CDCl3) δ 1.36 (3H, t, J=7.3 Hz), 1.53-1.91 (8H, m), 2.87 (3H, s), 3.41 (1H, m), 4.10 (2H, q, J=7.3 Hz), 5.45 (2H, s), 7.23-7.36 (2H, m), 7.58-7.75 (2H, m), 7.88 (1H, s); MS (ES+) m/e 422 [MH]+. Anal. Found C, 62.56; H, 5.67; N, 23.18%. C22H24FN7O requires C, 62.69; H, 5.74; N, 23.26%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:22])[CH:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].C1C(=O)N([Br:36])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:21][C:19]1[CH:20]=[C:11]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]=[C:13]([CH3:22])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(-c2cnc(OC)c(OC)c2)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cc(-c2cnc(OC)c(OC)c2)cc1CBr
Temperature: 25 °C
Yield: 76.3 %

Procedure:
As shown in step 6-ii of Scheme 6, Compound 2022 (710 mg, 2.36 mmol) was dissolved in CCl4 (20 mL) and K2CO3 (651 mg, 4.71 mmol), NBS (461 mg, 2.59 mmol), and benzoyl peroxide (57 mg, 0.24 mmol) were added. The reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was filtered and the solid washed with CCl4. The filtrate was concentrated to an oil under reduced pressure and purified by silica gel chromatography to provide methyl 2-(bromomethyl)-4-(5,6-dimethoxy-3-pyridyl)-6-methyl-benzoate (Compound 2023, 685 mg, about 70% pure). This compound was used in subsequent reactions as is.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH3:24])[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc(NC(=O)OC(C)(C)C)c(-c2ccccc2C)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CI
Product: CSc1ncc(N(C)C(=O)OC(C)(C)C)c(-c2ccccc2C)n1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 1.9 g (5.73 mmol) (2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 15 ml N,N-dimethylformamide 0.29 g (7.45 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.57ml (9.17 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was distributed between 75 ml H2O, 75 ml brine and 75 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 75 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 15:1) to give 1.95 g (98%) methyl-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert.-butyl ester as a colorless oil. MS (TSP): 345 (M+).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH2:29]([O:31][CH2:32]OCC)[CH3:30].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:29]([O:31][CH2:32][O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)[CH3:30]
Reactant: CCOCOCC
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
20 g. of cholesterol is dissolved in 300 ml. of formaldehyde diethylacetal, combined under agitation at room temperature with 30 g. of kieselguhr and in incremental portions with 15 g. of phosphorus pentoxide, and agitated for 4 hours at room temperature. The product is filtered off from the insoluble matter, washed with formaldehyde diethylacetal, and the solvent is distilled off under vacuum. The residue is crystallized at 0° C. After adding sodium bicarbonate solution, the crude product is vacuum-filtered, washed with water, and, after drying, 22.5 g. of 3β-ethoxymethoxy-5-cholestene is obtained. The compound, recrystallized from ethyl acetate, melts at 64°-66° C.
Reaction SMILES: C(O[C:4](=[O:30])[C@H:5]([O:7][C:8]1[N:29]=[CH:28][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=3)[CH3:6])C.O.[OH-].[Li+].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O.C(OCC)(=O)C>[CH:25]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:28]=[N:29][C:8]([O:7][C@H:5]([CH3:6])[C:4]([NH2:35])=[O:30])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1)([CH3:27])[CH3:26]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)[C@@H](C)Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@H](C)C(N)=O)cc1OCC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of (R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid ethyl ester (70 mg, 0.17 mmol) in methanol (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (23 mg, 0.58 mmol) and the reaction mixture stirred at 50° C. for 1 h. The reaction mixture was concentrated in vacuo and the resultant residue azeotroped with acetonitrile (3×20 mL). The residue was dissolved in DMF (3 mL), HATU (220 mg, 0.58 mmol), ammonium chloride (46 mg, 0.86 mmol) and triethylamine (120 μL, 0.86 mmol) added and the reaction mixture stirred at RT for 1.5 h. The reaction mixture was diluted with ethyl acetate, washed with water, extracting with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield 446 as a white solid (28 mg, 43%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR (400 MHz, d6-DMSO) 9.05 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.38 (1H, br s), 7.05 (1H, br s), 6.41 (1H, s), 5.87 (1H, sept, J=6.6 Hz), 5.17 (1H, q, J=6.8 Hz), 4.60-4.43 (4H, m), 1.50-1.34 (9H, m)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN1CCOCC1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]([CH2:35][O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:33]([Cl:43])[N:32]=[C:31]2[CH2:44][CH2:45][CH2:46][CH3:47])=[CH:25][CH:24]=1)(O)=[O:15].[O:48]([NH2:50])[CH3:49]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[CH3:49][O:48][NH:50][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][N:30]2[C:34]([CH2:35][O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:33]([Cl:43])[N:32]=[C:31]2[CH2:44][CH2:45][CH2:46][CH3:47])=[CH:27][CH:28]=1)=[O:15]
Reactant: CON
Reactant: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)NOC)cc1
Reaction time: 0.33 h

Procedure:
A solution of 0.24 ml of oxalyl chloride in 5 mL of chloroform was added dropwise to a solution of 1 mL of dimethylformamide in 4 mL of chloroform at -20°. After this solution had been stirred at -20° for 20 minutes, 0.28 mL of N-methylmorpholine was added followed by 1.21 g of 1-[(2'-carboxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. After another 20 minutes at -20°, 0.55 ml of N-methylmorpholine and 1.35 mL of methoxylamine were added to the mixture. The reaction mixture was warmed slowly to 25°, stirred at 25° for 4 hours, and finally refluxed for 40 hours. After cooling the mixture was diluted with ethyl acetate. The resulting solution was washed with 10% hydrochloric acid, water, 10% sodium bicarbonate solution and brine. Finally the solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol/chloroform) furnished 0.21 g of 1-[(2'-methoxyaminocarbonylbiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDCl3) δ7.85 (s, 1H); 7.63 (d, 1H); 7.53-7.33 (m, 5H); 7.05 (d, 2H); 5.20 (s, 2H); 4.67 (s, 2H); 4.47 (s, 2H); 3.63 (m, 5H); 3.55 (m, 2H); 3.36 (s, 3H); 2.56 (t, 2H); 1.67 (m, 2H); 1.32 (m, 2H); 0.87 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:47])[C:32]([C:45]#[N:46])=[CH:33][C:34]3([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]3([NH2:37])[CH2:36][CH2:35]3)[C:45]#[N:46])=[O:47])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)NC1(C=C(C#N)C(=O)N2CCC[C@@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC(=CC1(N)CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reaction time: 5 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl N-[1-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]cyclopropyl]carbamate (27 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL). The solution was stirred for 5 hrs. and then concentrated. The residue was purified by prep-TLC (5% MeOH/DCM) to provide 2.68 mg (12%) of the title compound. MS (pos. ion) m/z: 539 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Product: NC(=O)c1ccnc(-c2cn(CC3CC3)cn2)c1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (PREPARATION 7) and cyclopropylmethyl bromide according to the procedure for the preparation of Example 124, part A. [M+H] Calc'd for C13H14N4O, 327. Found, 327.
Reaction SMILES: Cl.[NH2:2]O.C([O-])=O.[Na+].[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]=O)[CH:19]=2)=[N:15][C:14]=1[CH3:27])=[O:12])[CH3:9].O>C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]#[N:2])[CH:19]=2)=[N:15][C:14]=1[CH3:27])=[O:12])[CH3:9]
Reactant: NO
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(C=O)c2)nc1C
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (35.82 g, 0.515 mol) and sodium formate (46.73 g, 0.687 mol) were added to a solution of ethyl-2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.343 mol) in formic acid (anhydrous, 300 mL) and the reaction mixture was heated to a temperature of about 100° C. for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40° C. and water was added to it. The reaction mixture was cooled to about 25° C. and stirred for about 1 hour. The solid obtained was filtered, washed with water and dried. The solid was then dissolved in acetone at about 50° C. and water was added slowly over a period of about 30 minutes. The mixture was cooled to about 25° C. and again stirred for about 1 hour. The solid thus obtained was filtered, washed with acetone:water (1:1) mixture and dried to obtain the title product. (Yield: 85 g, 85.9%)