Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3].[CH2:20]([O:27][CH2:28][C:29]1[CH:34]=CC=C[CH:30]=1)[C:21]1[CH:26]=CC=C[CH:22]=1.OCC(C)(C)C=O>>[CH3:22][CH:21]([CH3:26])[CH2:20][O:27][CH2:28][CH:29]([CH3:34])[CH3:30]
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: CC(C)(C=O)CO
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: CC(C)COCC(C)C

Procedure:
This isomerization reaction has been examined to a very large extent with regard to its mechanism and action of catalysts (J.Amer.Chem.Soc. 84, 3307 (1962)) and it was found that acidic catalysts are required for an isomerization and that of a great number of substances tested only silica gel and aluminum silicate in the form of pumice may practically be used as catalysts. But the activity and selectivity of these catalysts are not yet satisfactory from the economical point of view. Thus, the benzyl ether of hydroxypivalaldehyde can be prepared in the most favorable case with pumice with a conversion of 90 molar % and a selectivity of 83.3 molar %, i.e. a yield of 75 molar %. For the 2-methylpropyl ether, the yield with the same catalyst is 69 molar %, with a conversion of 84 molar % and a selectivity of 82.1 molar %, whereas the methyl ether is formed only in a yield of 38 molar %. When SiO2 is used as catalyst instead of pumice, the yield of the benzyl ether is even markedly lower, i.e. 46 molar %.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2cn(CCO)c(C3CCNCC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[4-(4-Fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1600.00 mg; 3.97 mmol; 1.00 eq.) in methanol 10 ml added 4.0M HCl in dioxane (9.91 ml; 39.65 mmol; 10.00 eq.), the reaction mixture was stirred at RT for 3 hrs, lc-ms showed clean desired, removed off solvent, got white solid as title compound.
Reaction SMILES: [Li].[C:2]1(OCC=C)[CH:7]=CC=C[CH:3]=1.C(O[C:15]([CH:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19]([CH3:25])=[C:18]1[CH2:26][CH3:27])=[O:16])C>O1CCCC1.CCOCC>[CH2:26]([C:18]1[CH:17]([C:15](=[O:16])[CH2:7][CH:2]=[CH2:3])[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][C:19]=1[CH3:25])[CH3:27]
Reactant: C=CCOc1ccccc1
Reactant: CCOC(=O)C1C(CC)=C(C)CCC1(C)C
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(=O)C1C(CC)=C(C)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A few crystals of diphenyl are added to a suspension, cooled to 5°-10° C and held under a nitrogen atmosphere, of 2.4 g (0.35 g-atoms) of finely cut lithium wire in 40 ml of absolute tetrahydrofuran. 2 ml of a solution of 9.4 g (70 mmol) of allyl phenyl ether in 10 ml of absolute ether are then added. After a greenish coloration sets in, the rest of the solution is added dropwise at -15° C. After completion of the addition, the mixture is stirred for 30 minutes at 0° C. The resulting allyl lithium solution is decanted off from excess lithium and transferred to a dropping funnel. This solution is added dropwise to a solution, cooled to -60° C and maintained under nitrogen, of 4.48 g (20 mmol) of 2-ethyl-3,6,6-trimethyl-2-cyclohexene-1-carboxylic acid ethyl ester in 40 ml of absolute ether. After completion of the addition, the mixture is left to warm to room temperature, poured on to ice-water and extracted with three portions of hexane. The combined hexane extracts are washed neutral with three portions of water, dried over sodium sulphate and evaporated. By fractional distillation of the residue there are obtained 3.75 g (85%) of 2-ethyl-3,6,6-trimethyl-1-[but-3-enoyl]-2-cyclohexene; boiling point 57°-58° C/0.04 mm Hg; nD20 = 1.4865.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:21]Br)[C:19]=1[Cl:20].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[Br:13][C:14]1[C:19]([Cl:20])=[C:18]([CH2:21][O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:17]=[N:16][CH:15]=1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Clc1c(Br)cncc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(OCc2cncc(Br)c2Cl)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (301 mg, 2.10 mmol) is dissolved in DMF (10 mL) and 60% sodium hydride in mineral oil (84 mg, 2.10 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. and 3-bromo-5-bromomethyl-4-chloro-pyridine (300 mg, 1.05 mmol) is added at that temperature. Then the mixture is warmed up to room temperature and stirred for 1 hr. Saturated NH4Cl aqueous solution (15 mL) is added, along with water (50 mL) and EtOAc (50 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×50 ml). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 112 mg of 1-[4-(5-bromo-4-chloro-pyridin-3-ylmethoxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:22]=2)[CH:6]=[C:7]([O:11]CC2C=CC(OC)=CC=2)[C:8](=[O:10])[CH:9]=1)[CH3:3].FC(F)(F)C(O)=O>ClCCl>[OH:11][C:7]1[C:8](=[O:10])[CH:9]=[C:4]([CH:2]([OH:1])[CH3:3])[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:22]=2)[CH:6]=1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4cncc5ccccc45)c3)c(C(C)O)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1cc(=O)c(O)cn1-c1cccc(-c2cncc3ccccc23)c1

Procedure:
To a 25 mL round bottom flask containing 2-(1-hydroxyethyl)-1-[3-(isoquinolin-4-yl)phenyl]-5˜[(4-methoxybenzyl)oxy]pyridin-4(1H)-one was added 5 mL 1:1 (v/v) dichloromethane:trifluoroacetic acid and the solution was stirred at room temperature for 30 minutes and turned deep red. Concentration under nitrogen stream, purification by reversed phase HPLC (2 cm×5 cm CI 8, acetonitrile-water gradient, 0.05% TFA added), and elution from an SCX column (50 g, sulfonic acid, rinsed with MeOH, eluted with 1 N N¾ in MeOH) afforded 5-hydroxy-2-(1-hydroxyethyl)-1-[3-(isoquinolin-4-yl)phenyl]pyridin-4(1H)-one. ′H NMR (599 MHz, DMSO, 75° C.): 6 9.35 (s, 1H); 8.51 (s, 1H); 8.22 (d, J−8.2 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.81 (t, J=7.7 Hz, 1H); 7.77-7.69 (m, 3H); 7.61 (s, 1H); 7.58 (d, J−7.8 Hz, 1H); 7.39 (s, 1H); 6.48 (s, 1H); 4.44 (q, J=6.4 Hz, 1H); 1.24 (d, J−6.4 Hz, 3H). HRMS (FT/ICR) calc 359.1390 (M+H)+ 359.1395 found.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:4]([C:21]2[C:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1.CCN(CC)CC.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH:39]1([CH2:38][O:37][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:21]=2[C:4]2[CH:5]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C:7]3[CH2:8][O:9][C:50](=[O:52])[NH:1][C:2]=3[N:3]=2)[CH2:40][CH2:41]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c(CO)c(N)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c3c(n2)NC(=O)OC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.5 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-{[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]amino}ethylcarbamate (0.050 g, 0.089 mmol) and Et3N (0.074 mL, 0.531 mmol) in THF (10 mL) was added triphosgene (0.013 g, 0.044 mmol) in one portion. The mixture was stirred at 0° C. for 1 hr, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (ethyl acetate) gave tert-butyl 2-[(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)-oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)amino]ethylcarbamate as colorless oil (0.036 g, yield; 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.C([Sn](CCCC)(CCCC)[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC.[Cl-].[Li+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:8][CH2:9][C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:23][C:6]2=3)=[CH:17][CH:18]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(-c3ncccn3)cc1N(c1ccc(Cl)cc1)CC2
Temperature: 100 °C
Yield: 5.1 %

Procedure:
Into a 25 mL sealed-tube evacuated and brimmed with nitrogen, was charged with a mixture of 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (Compound 13; 40 mg, 0.10 mmol), 2-(tributylstannyl)pyrimidine (56.8 g, 0.15 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.2 mg, 0.01 mmol), lithium chloride (6.5 mg, 0.15 mmol) and toluene (2 mL). The mixture was heated for 12 hours at 100° C. The mixture was concentrated in vacuo, partitioned with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by prep-HPLC (Phenomenex C18 (150 mm*21.2 mm*5 um), acetonitrile/water=1:100 (0.1% formic acid), flow rate: 30 mL/min) to yield 6-(4-chlorophenyl)-1-methyl-8-(pyrimidin-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a white solid (2 mg, 5%).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]([C:5]([OH:7])=O)[CH3:4].C(N1CCOCC1)C.ClC(OCC(C)C)=O.O1CCCCC1ONC([C@H]([C@@H:51]([CH2:60][CH:61]([CH3:63])[CH3:62])[C:52]([NH:54][NH:55][CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])C/C=C/C1C=CC=CC=1)=O>O1CCCC1.C(OCC)(=O)C>[CH2:56]([N:55]([C:5](=[O:7])[C@H:3]([CH3:4])[N:2]([CH3:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:54][C:52](=[O:53])[CH2:51][CH2:60][CH:61]([CH3:63])[CH3:62])[CH:57]([CH3:59])[CH3:58]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.233 g of N-methyl-N-tert.-butoxycarbonyl-L-alanine in 10 ml of tetrahydrofuran was cooled to −10° C. and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred for a further 10 minutes at −10° C. and then treated with 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide. The mixture was allowed to warm to 0° C. and stirring was continued for 45 minutes. The mixture was then diluted with ethyl acetate and washed in sequence with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine. Drying over magnesium sulphate and evaporation gave 0.608 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(N-methyl-N-tert.-butoxycarbonyl-L-alanyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:17]([CH:18]=[C:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:16][C:15]=3[C:31]([F:34])([F:33])[F:32])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.[H][H].[Pd]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([C:31]([F:32])([F:34])[F:33])=[CH:16][C:17]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])=[CH:25][C:26]=3[C:27]([F:29])([F:30])[F:28])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=C4CCOC4=O)cc3C(F)(F)F)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC4CCOC4=O)cc3C(F)(F)F)cc12

Procedure:
0.2 g (0.38 mmol) of benzylidene compound from Example 24 are dissolved in 100 ml of methanol and hydrogenated with hydrogen for 18 hours in the presence of palladium on active carbon. The catalyst is filtered off through kieselguhr and the filtrate is concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 in the isocratic gradient mode using toluene/ethyl acetate (10:1).
Reaction SMILES: CS(C)=O.[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH2:14][C:15]#[N:16])[CH:9]=[CH:10][CH:11]=2)[O:6]1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>O>[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH:14]([C:15]#[N:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][CH:11]=2)[O:6]1
Reactant: CCCCCBr
Reactant: N#CCc1cccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(C#N)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Into 5 ml of dimethylsulfoxide, was added 0.26 g (1.6 mmol) of 2,3-methylenedioxyphenylacetonitrile, then, 0.24 g (1.6 mmol) of n-pentyl bromide and a 50% aqueous solution of sodium hydroxide were added dropwise thereinto simultaneously under cooling with ice. After 30-minute stirring at room temperature, the mixutre was added with water and extracted with ether. The ether extract was dried over magnesium chloride and then the solvent was evaporated off to obtain 0.30 g of oily 1-(2,3-methylenedioxyphenyl)hexane carbonitrile.
Reaction SMILES: C(O[CH:5]1[CH2:31][C:30](=[O:32])[CH:29]([CH2:33][CH:34]=[CH2:35])[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][CH:50]2[CH2:55][CH2:54][CH:53]([O:56][Si:57]([C:70]([CH3:73])([CH3:72])[CH3:71])([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH:52]([O:74][CH3:75])[CH2:51]2)[CH:6]1[CH3:77])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[CH2:33]([CH:29]1[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][CH:50]2[CH2:55][CH2:54][CH:53]([O:56][Si:57]([C:70]([CH3:73])([CH3:72])[CH3:71])([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:52]([O:74][CH3:75])[CH2:51]2)[CH:6]([CH3:77])[CH:5]=[CH:31][C:30]1=[O:32])[CH:34]=[CH2:35]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(OC)C3)C(C)C(OC(C)=O)CC1=O)C(C)CC2OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 14-acetoxy-17-allyl-12-[2-(4-tert-butyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (43.8 mg) in tetrahydrofuran (1.5 ml) was added potassium carbonate (ca 100 mg) at room temperature and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with diethyl ether and the resulting solution was washed with a saturated aqueous ammonium chloride, water and an aqueous sodium chloride successively, and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 3:2 v/v) to give 17-allyl-12-[2-(4-tert-butyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (30 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12]CC)=[O:11])=[CH:5][N:4]=1.[OH-].[Na+]>O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(NC)nc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ncc(C(=O)O)c(O)n1

Procedure:
2-Methylamino-5-ethoxycarbonyl-4-hydroxypyrimidine (360 mg 1.9 mmol) was hydrolysed in boiling water (10 ml) with NaOH (0.19 g, 4.7 mmol) for 2 h. Cooling and acidification to pH 2 yielded the named product as a precipitate (261 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[NH:18])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28].N1C=CNC1>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=3)[CH2:25][C:26]([OH:31])([C:27]([F:30])([F:29])[F:28])[N:18]=2)=[N:6][CH:7]=1
Reactant: CSc1ccc(NC(=N)c2ccc(C)cn2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: C1=CNCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C)cn2)cc1

Procedure:
To a mixture of the amidine of step 2 (10 g, 52.41 mmol) and sodium bicarbonate (8.6 g, 103 mmol) in isopropanol (1200 ml), 3-bromo-1,1,1-trifluoroacetone (10 g, 52 mmol) was added. After heating at reflux for 22 hours, the reaction mixture was cooled and filtered. The residue was dissolved in methylene chloride and washed water than brine. The organic extracts were dried (MgSO4), filtered and concentrated. The crude mixture was purified by chromatography (silica gel, 100% ethyl acetate) to give. the desired dihydro-imidazole (5.1 g): Anal Calc'd. for C17H16N3SOF3: C, 55.58; H, 4.39; N, 11.44. Found: C, 55.54; H, 4.35; N, 11.20.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:34])[C:10]([O:13][C:14]3[CH:15]=[C:16]([C:26]4[NH:30][C:29]([C:31]([OH:33])=O)=[CH:28][CH:27]=4)[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[Cl:36][CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C.Cl.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:34])[C:10]([O:13][C:14]3[CH:15]=[C:16]([C:26]4[NH:30][C:29]([C:31]([NH:39][CH2:38][CH2:37][Cl:36])=[O:33])=[CH:28][CH:27]=4)[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 23.2 %

Procedure:
5-(3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]phenyl)-1H-pyrrole-2-carboxylic acid (800 mg, 1.65 mmol) synthesized in Example (71a) was dissolved in dichloromethane (10.0 mL), and 2-chloroethylamine hydrochloride (300 mg, 2.59 mmol), WSCI.HCl (630 mg, 3.29 mmol) and 4-dimethylaminopyridine (400 mg, 3.27 mmol) were added, followed by stirring at room temperature under nitrogen atmosphere for 2.5 days. To the reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate) to afford the desired compound (210 mg, yield 23%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.CC(C)([O-])C.[Na+]>[Pd].O1CCOCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(N3CCCC3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 g (0.18 mmol) of 1-(1-allyl-6-bromo-1H-indol-3-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol, 28.0 mg (0.4 mmol) of pyrrolidine, 5.0 mg of Pd catalyst (prepared according to a procedure described in Org. Lett. 2003 14 2413-2415), and 35.0 mg (0.36 mmol) of sodium tert-butoxide in 10 mL of dioxane was warmed at 90° C. After 2 hours, the mixture was cooled to room temperature, filtered through CELITE® filter aid, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate in hexanes (30-80% gradient). The major fractions were combined and concentrated in vacuo to afford 21.0 mg 21.4%) of the title compound. MS m/z 534.5 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10][O:9]1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:8]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][O:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC2(CCN1)COC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (Description 69, 80 mg, 0.625 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate (3 mL) and dichloromethane (5 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (3×3 mL) and the combined organic fractions were poured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (8 mg, 17%). m/z (ES+) 128 (M+1).