Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14]2)[C:3]=1[C:4]([OH:6])=[O:5].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:26]1([CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][O:19][C@H:15]2[CH2:16][CH2:17][CH2:18][C@@H:13]([O:12][CH2:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=3[C:4]([OH:6])=[O:5])[CH2:14]2)[C:39]([NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc(CO[C@@H]2CCC[C@H](OCCNCCCc3ccccc3)C2)c1C(=O)O
Solvent: CN(C)C=O
Product: Cc1cccc(CO[C@@H]2CCC[C@H](OCCN(CCCc3ccccc3)C(=O)Nc3ccccc3)C2)c1C(=O)O
Reaction time: 0.5 h

Procedure:
160 mg of 2-methyl-6-{(1R,3S)-3-[2-(3-phenylpropylamino)ethoxy]cyclohexyloxymethyl}benzoic acid are dissolved in 2 ml of dimethylformamide, and 0.1 ml of phenyl isocyanate is added. After 30 minutes, the reaction mixture is purified by RP-HPLC. This gives 54 mg of 2-{(1R,3S)-3-[2-(1-[3-phenylpropyl]-3-phenylureido)ethoxy]cyclohexyloxymethyl}-6-methylbenzoic acid as a white lyophilizate. C33H40N2O5 (544.70), MS(ESI): 545 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH:18](OCC)(OCC)[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])=[CH:18][O:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
A mixture of (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (8.3 g, 32 mmol) and triethyl orthoformate (16 mL, 96 mmol) in acetic anhydride (20 mL) was refluxed under N2 for 16 h. Solvents were removed by distillation (keep the temperature of oil bath below 180° C.). The residue was purified by chromatography on silica gel (1:1 ethyl acetate/hexanes) to provide the desired product as a mixture of isomers (a mixture of trans- and cis-isomers, 5.3 g, 53%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.O>C1COCC1>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 2,2-difluorobenzo[d][1,3]dioxol-5carbaldehyde (125 g, 0.67 mol) in anhydrous THF (400 mL) was added NaBh4 (28 g, 0.74 mol) in portions at 0° C. The mixture was stirred for 1 h at 0° C., then poured into 500 mL of water. The mixture was extracted with ethyl acetate (200 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo to give (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol as colorless oil (120 g, 95%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:24][CH:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH:25]([OH:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)OCCN1CCSc2ccccc21
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(O)Cc1ccc(OCCN2CCSc3ccccc32)cc1
Yield: 16.3 %

Procedure:
The title compound (1.9 g, 17%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethyl methanesulfonate (8.2 g, 30.0 mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol) using conditions analogous to that described in preparation 2.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:23][CH3:24])=O>CO.C(Cl)Cl>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:23][CH3:24]
Reactant: CSc1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Solvent: ClCCl
Solvent: CO
Product: CSc1c(N)nc2ccc(C(=O)c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
The 2-trifluoroacetamido-3-methylthio-6-benzoyl-imidazo[1,2-a]pyridine (100 mg, 263 mmol) was dissolved in 20 mL of a mixture of MeOH/CH2Cl2 1:1, and 5 g of silica gel was added. The mixture was stirred at RT for 2 days. The residue was filtered and washed with CH2Cl2 and the solution was concentrated in vacuo to give 63 mg (850%) of a yellow solid. 1H-NMR (200 MHz, CDCl3) d 2.12 (s, 3H, SMe), 4.40 (bs, 2H, NH2), 7.46-7.80 (m, 7H, ArH+H7+H8), 8.68 (d, J57=1.7, H5). 13C-NMR (50 MHz, CDCl3) d 18.0 (SMe), 95.0, 122.7, 125.8, 127.7, 128.5, 129.6, 132.6, 137.4, 145.3, 156.1, 193.5.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][N:9]([CH3:18])[C:8]=1[CH3:19].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1>O1CCCC1>[F:30][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][N:9]([CH3:18])[C:8]=1[CH3:19]
Reactant: Cc1c(Br)c(-c2ccccc2)cn1C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(F)c(-c2ccccc2)cn1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
n-Butyllithium (2.06 mL, 1.6M solution, 3.30 mmol) was added to a solution of 3-bromo-1,2-dimethyl-4-phenyl-pyrrole (550 mg, 2.20 mmol) in tetrahydrofuran (10 mL) at −78° C. and the reaction mixture was stirred at −78° C. for 30 min. A solution of n-fluorodibenzene sulfonamide (901 mg, 2.86 mmol) in tetrahydrofuran (8 mL) was added to the reaction mixture at −78° C. and the reaction mixture was stirred at this temperature for another 1 h. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h after which time the reaction mixture was quenched with dilute HCl and evaporated to dryness. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by preparative HPLC afforded 3-fluoro-1,2-dimethyl-4-phenyl-pyrrole (160 mg, 39%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH:14]=O)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:11]/[CH2:10][C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)(CC)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CCC(CC)(CC)C/C=N/CC(=O)OC(C)(C)C
Yield: 100.7 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted with 3,3-diethyl-pentanal (1 g, 7 mmol) in CH2Cl2 at room temperature for 5 h to give [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.8 g, 100%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:21]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (418 mg) obtained in Example 6, steps 1-6, vinylboronic acid pinacol ester (0.221 mL), dichlorobis(triphenylphosphine)palladium (42 mg) and potassium carbonate (498 mg) in DME-water (1:1, 10 ml,) was stirred at 85° C. for 1.5 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (239 mg, 68%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=2)[CH:19]=[N:18]1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:26][C:23]3[CH:24]=[C:25]4[C:20]([CH:19]=[N:18][NH:17]4)=[CH:21][CH:22]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc2cn[nH]c2c1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc3cn[nH]c3c2)nc(N)n1
Yield: 73 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 1H-indazol-6-yl-amine provided the title compound (73% yield). 1H NMR (DMSO-d6) δ 2.37 (s, 3H, CH3), 6.17 (s, 1H, Ar), 6.35 (s, 2H, NH2), 7.30-7.33 (m, 2H, Ar), 7.37 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.43 (d, 1H, J=2.3 Hz, Ar), 7.64 (d, 1H, J=8.6 Hz, Ar), 7.95 (s, 1H, Ar), 8.04 (s, 1H, Ar), 9.33 (s, 1H, NH), 12.80 (s, 1H, Ar).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([O:15][CH2:21][CH:20]=[CH2:19])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
N-tert-Butoxycarbonyl (4R)-hydroxyproline (9.25 g, 40 mmol) was added to a solution of 60% sodium hydride (3.36 g, 84 mmol) in 100 ml of anhydrous tetrahydrofuran and stirred for 2 hours at room temperature. Allyl bromide (6.9 ml, 80 mmol) was added to the mixture and refluxed for 6 hours. The mixture was quenched with the addition of ice chips, then additional water was added and the mixture was washed with hexane. The aqueous layer was acidified with 10% sodium hydrogen sulfate and extracted with ethyl acetate (2×150 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give 5 g of the title product with no further purification. 1NMR (CDCl3 ; exist as rotamers) δ 5.92-5.82 (1H, m), 5.3-5.14 (2H, m) 4.5-4.31 (1H, m), 4.16-4.05 (1H, m), 4.04-3.9 (1H, m), 3.79-3.5 (3H, m), 2.43-2.2 (1.5H, m), 2.15-2.10 (0.5H, m), 1.45 (4.5H, s), 1.35 (4.5H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1I.[F:12][C:13]([F:18])([F:17])C([O-])=O.[Na+]>CN1CCCC1=O.O.[Cu]I>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:18])([F:17])[F:12]
Reactant: O=C([O-])C(F)(F)F
Reactant: Cn1c(I)cc2ccccc21
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1c(C(F)(F)F)cc2ccccc21
Temperature: 160 °C
Yield: 37 %

Procedure:
A mixture of 1-methyl-2-iodoindole (4.40 g, 17.3 mmole), sodium trifluoroacetate (24.0 g, 176.5 mmole) and copper(I) iodide (17.1 g, 89.8 mmole) in N-methylpyrrolidone is heated at 160° C. for 6 hours, cooled to room temperature, diluted with water and filtered through diatomaceous earth to remove copper salts. The filtrate is extracted with ether. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 4:1 hexanes:ethyl acetate as eluent to give the title product as a pale yellow oil which crystallized on standing, 119 g (37% yield), mp 28°-32° C., identified by IR, 1HNMR and 19FNMR analyses.
Reaction SMILES: [Mg].[CH3:2]I.[C:4]([C:8]1[CH:19]=[CH:18][C:11]([C:12]([CH3:17])=[C:13]([CH3:16])[CH:14]=[O:15])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[Cl-].[NH4+]>CCOCC.O>[C:4]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([CH3:17])=[C:13]([CH3:16])[CH:14]([OH:15])[CH3:2])=[CH:18][CH:19]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C=O)=C(C)c1ccc(C(C)(C)C)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(=C(C)C(C)O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A Grignard solution is prepared in the usual manner from 10.7 g of magnesium in 30 ml of absolute ether and 68.8 g of methyl iodide in 100 ml of absolute ether. To this solution are added dropwise at 20°-25° C. over a period of 15-20 minutes 56.1 g of p-tert.butyl-α,β-dimethyl-cinnamaldehyde. After cooling to room temperature, the mixture is cautiously poured on to 200 g of ice and 150 g of technical ammonium chloride in 500 ml of water are added. The organic phase is separated, washed with water and sodium bicarbonate solution, dried over sodium sulphate and concentrated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-1,2,3-trimethyl-allyl alcohol of boiling point 143°-148° C./0.001 Torr.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8])(=O)C.[OH-].[NH4+].Cl>O>[SH:4][CH2:5][CH2:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8]
Reactant: CC(=O)SCCC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)CCS
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
trans-2-[3-(Acetylthio)-1-oxopropyl]cyclohexanecarboxylic acid (3.0 g., 11.6 mmol.) is added to a cold mixture of 5 ml. of concentrated ammonium hydroxide and 5 ml. of water under argon. The mixture is stirred at room temperature for 30 minutes. While cooling to 0°, the solution is acidified with concentrated hydrochloric acid. The mixture is extracted four times with ethyl acetate. The extracts are dried and the solvent is removed in vacuo. The oily product is chromatographed on 90 g. of silica gel eluting with ethyl acetate. A total of 2.2 g. (88%) of material is obtained which is contaminated with some more polar material. Chromatography of 1.9 g. of this material on 60 g. of silica gel and eluting with chloroform and 2% methanol in chloroform gives 1.4 g. of trans-2-(3-mercapto-1-oxopropyl)cyclohexanecarboxylic acid, recrystallized from isopropyl ether-hexane, 1.0 g. (46%), m.p. 71°-74°.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH3:30])=[C:7]([C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]([NH:10][C:11]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:19][CH3:20])=[O:9])[CH2:2][CH2:3][CH3:4].CO[C:33](OC)(N(C)C)[CH3:34].CN(C)C>C1C=CC=CC=1>[CH2:1]([N:5]1[C:33]([CH3:34])=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:21](=[O:29])[C:7]([C:8]([NH:10][C:11]2[C:12]([CH2:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH3:18])=[O:9])=[C:6]1[CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: COC(C)(OC)N(C)C
Reactant: CCCCNC(C)=C(C(=O)Cc1ccccc1)C(=O)Nc1c(CC)cccc1CC
Agent: CN(C)C
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)Nc2c(CC)cccc2CC)c(=O)c(-c2ccccc2)c1C
Yield: 43.4 %

Procedure:
A mixture of 4.07 g (10 mmol) of the resulted 3-butylamino-N-(2,6-diethylphenyl)-2-phenylacetyl-2-butenic acid amide, 4.00 g (30 mmol) of N,N-dimethylacetamide dimethyl ketal, 0.4 ml of trimethylamine and 20 ml of benzene was refluxed for 3 hours under nitrogen atmosphere. The residue, obtained by concentrating the reaction mixture under vacuo, was column-chromatographed on silica gel to afford 1.87 g of the title compound, as oil.
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:49]1[N:50]=[CH:51][N:52]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][CH2:61]O)=[CH:56][CH:55]=2)[CH:53]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:4]12[N:7]([C:8](=[O:48])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:47])[CH2:30][N:31]([CH2:61][CH2:60][C:57]3[CH:56]=[CH:55][C:54]([N:52]4[CH:53]=[N:49][N:50]=[CH:51]4)=[CH:59][CH:58]=3)[S:32]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=3[N+:44]([O-:46])=[O:45])(=[O:33])=[O:34])([CH3:10])[CH3:11])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: OCCc1ccc(-n2cnnc2)cc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN(CCc2ccc(-n3cnnc3)cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of (S)-N-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl 2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-2,4-dinitrobenzenesulfonamide (0.197 g in 6 mL dry benzene:N,N-dimethylformamide, 2:1) was added 0.083 g 2-(4-[1,2,4]triazol-4-yl-phenyl)ethanol followed by 0.115 g triphenylphosphine and 0.069 mL of diethyl azodicarboxylate added dropwise. After 1.5 hours, the mixture was concentrated and the crude reaction product purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (0.246 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[Cl:25]Cl.O>CCOCC>[Cl:25][C:5]1[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:22]=[CH:21][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: ClCl
Reactant: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
Methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate is stirred with a catalytic amount of ferric chloride. The reaction mixture was heated to 70° C. under a continuous stream of chlorine gas. After 2.5 hours, the mixture was taken up in ether, shaken with water and the organic phase was dried over MgSO4. The ether was evaporated to afford methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate. NMR (CDCl3)δ8.2-7 (m,6) 4.0 (2,3). TLC (40% ether/hexane) Rf ≈.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31][N:48]4[CH2:49][CH2:50][CH:45]([OH:44])[CH2:46][CH2:47]4)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Reactant: OC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC(O)CC2)C1

Procedure:
The title compound is prepared in analogy to Example 116 from cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanol of Example 124, p-toluenesulfonyl chloride and 4-hydroxypiperidine (Fluka, Buchs, Switzerland). Analytical HPLC-MS: tR=1.49 min; ES-MS: m/eo=512.48.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].[CH2:14]([OH:17])[CH2:15]Br.O>CN(C)C=O>[N+:9]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][CH:14]([OH:17])[CH3:15])([O-:11])=[O:10]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)Oc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2.5 mols (434 g) of 4-chloro-3-nitrophenol are dissolved in 1,300 ml of dimethylformamide heated to 70° C. beforehand. 3 mols of powdered potassium hydroxide (210 g of 80% pure potassium hydroxide) are added to this solution and 3 mols (534 g) of glycol bromohydrin are then introduced in the course of 30 minutes, with stirring, whilst keeping the temperature at 70° C. When the addition has ended, the reaction medium is kept at 70° C. for 1 hour. 1 mol of powdered potassium hydroxide (70 g of 80% pure potassium hydroxide) and 1 mol of glycol bromohydrin (178 g) are then added. After heating for 1 hour, a further 1 mol of potassium hydroxide and 1 mol of glycol bromohydrin are added. The heating is continued for a further 1 hour and the cooled reaction medium is then poured into 7.5 liters of iced water. The expected product precipitates. It is filtered off and washed carefully with a 3N solution of sodium hydroxide and then with water. After drying in vacuo, it melts at 96° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19].[OH-].[K+].I[CH3:23]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])=[CH:4][C:3]=1[CH2:17][CH2:18][O:19][CH3:23]
Reactant: CI
Reactant: C[Si](C)(C)CCOCOc1ccc(Br)c(CCO)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCCc1cc(OCOCC[Si](C)(C)C)ccc1Br
Reaction time: 16 h
Yield: 59 %

Procedure:
2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g, 6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and the solution stirred for 16 h. The reaction was diluted with water (50 mL) and extracted with ether (2×40 mL). Organics were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (10% ether/hexanes) gave 1.28 g of {2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.7 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][CH2:21][CH:22]([OH:25])[CH2:23][CH3:24]>>[CH2:21]([CH:22]([O:25][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1)[CH2:23][CH3:24])[CH3:20]
Reactant: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Product: CCC(CC)Oc1nc(C)nc(Cc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared by the method analogous to that in Example 32 starting with 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine and 3-pentanol. White crystals, mp. 82–84° C.