Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32]([N:34]4[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]4)=[O:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)=[O:33])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)N4CCC(O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(=O)N3CCC(O)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
A solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone (0.109 g, 0.157 mmol) in TFA (7.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature and concentrated to about 50% of the original volume under a stream of argon. A few pieces of ice were added, and then a saturated solution of NaHCO3 was added slowly until pH 7 was reached. The precipitate was isolated by filtration, and the filtercake was washed with water. The solid was suspended in 3 mL of MeOH and 1 mL of THF, then 0.5 mL of 1 N NaOH was added. The suspension was stirred at room temperature for 10 min. The solid was isolated by filtration and dried to give (5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone (0.0406 g, 0.089 mmol, 56.9% yield) as an amorphous yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.08 (s, 1H); 8.85 (d, J=2.3 Hz, 1H); 8.41 (dd, J=4.8, 2.2 Hz, 2H); 8.35 (dd, J=12.6, 2.2 Hz, 1H); 7.96 (br. s., 1H); 7.81 (br. s., 1H); 4.79 (d, J=3.7 Hz, 1H); 3.95 (s, 3H); 3.74 (s, 3H); 3.20-3.27 (m, 2H); 2.44 (s, 3H); 1.76 (br. s., 2H); 1.40 (br. s., 2H). m/z (ESI, +ve ion) 455.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(Cl)C.[C:26]1([S:36](Cl)(=[O:38])=[O:37])[C:27]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[C:9]([O:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([N:1]2[S:36](=[O:38])(=[O:37])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]2(=[O:34])=[O:33])=[CH:3][CH:4]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1

Procedure:
Following the General Procedure (Scheme 1), tert-butyl 4-aminobenzoate, 1, (1.0 g, 5.17 mmol), triethylamine (1.8 mL, 12.9 mmol), dichloroethane (75 mL), benzene-1,2-disulfonyl dichloride (1.7 g, 2.88 mmol) and dichloroethane afforded tert-butyl-4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoate, 5, (0.39 g, 38%).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1cccc(Cl)c1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccc(Cl)c1

Procedure:
A solution 2-Chloro-nicotinonitrile (5.0 grams, 36.1 mmole), cesium carbonate (23.5 grams, 72.2 mmole) and 3-chlorophenol (4.65 grams, 36.1 mmole) in dimethylformamide (100 ml) was heated to 80° C. over night. The mixture was cooled and poured into 500 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a white solid (8.21 g). M.P. 88-90° C.; Anal. calcd. for C12H7N2OCl: C, 62.49; H, 3.06; N, 12.15. Found: C, 62.43; H, 3.00; N, 12.13.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:9]1([CH2:14][CH2:15][OH:16])[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:16][CH2:15][CH2:14][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCn1ccnc1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)OCCn1ccnc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In a nitrogen atmosphere, 148 g of caproyl chloride was added dropwise to a mixture of 112 g of 2-(1H-imidazol-1-yl)ethanol, synthesized in Synthesis Example 1, 121 g of triethylamine and 1,000 g of methylene chloride at 0° C. Then the reaction mixture was heated at 20° C. and stirred for 5 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by vacuum distillation, obtaining 189 g of 2-(1H-imidazol-1-yl)ethyl caproate (boiling point 127° C./20 Pa, yield 90%).
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[NH:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[CH3:22][CH:23]([CH3:34])[C:24](=O)[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:21]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=[C:24]([CH:23]([CH3:22])[CH3:34])[N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(C)C)nc(Nc2ccc(-n3cnc(C)c3)c(F)c2)n1
Temperature: 170 °C
Yield: 20 %

Procedure:
A mixture of N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine nitrate (719 mg, 2.0 mmol), ethyl 5-methyl-2,4-dioxo-hexanoate (372 mg, 2.0 mmol) and potassium carbonate (138 mg, 1.0 mmol) in ethanol (5 mL) was heated in a sealed tube in a microwave oven to 170° C. for 0.5 h. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and with brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent to give the title compound (153 mg, 20%) as a light yellow solid. MS ISP (m/e): 384.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): 8 (ppm)=8.11 (dd, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.25-7.30 (2H), 6.94 (s, 1H), 4.48 (q, 2H), 3.05 (m, 1H), 2.31 (s, 3H), 1.46 (t, 3H), 1.36 (d, 6H).
Reaction SMILES: [C:1]1([C:7]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[N+:41]([O-])=O)[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.O.NN>[Pd].C(OCC)(=O)C>[C:50]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[NH2:41])[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:23][CH:24]=3)=[N:11][N:10]=[N:9]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(c1ccc([N+](=O)[O-])c(OCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1)N1CCOCC1
Agent: [Pd]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)N2CCOCC2)cc1OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 116.5 %

Procedure:
A solution of the compound ([3]-(33)-587) (0.60 g) prepared in Example 37, ethanol (150 ml), and ethyl acetate (40 ml) was stirred at 70° C. for 15 minutes. After 10% Pd/C (0.10 g) and hydrazine monohydrate (1 ml) were added to the solution, the mixture was stirred at 70° C. for 1 hour. The insolubles were filtered through celite, and the filtrate was concentrated to obtain colorless foam (0.67 g). The product was purified by silica gel column chromatography (Kieselgel 60=80 g, chloroform/ethyl acetate=13/7) to obtain the compound ([3]-(34)-587) (0.09 g).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH2:16][C:5]1=2)#[N:2].[ClH:19].C(OCC)(=O)C>[Pd].C(O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH2:14][C:15]([CH3:17])([CH3:18])[CH2:16][C:5]1=2
Reactant: CCOC(=O)c1cc2c(n1CC#N)CC(C)(C)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(n1CCN)CC(C)(C)C2
Reaction time: 6 h

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 2.0 g dry weight), 103c (4.5 g, 18 mmol), 12% hydrochloric acid (9.2 mL, 37 mmol), ethyl acetate (80 mL) and ethanol (52 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Diatomaceous earth filtration agent (Celite® 521, 10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The crude residue 103d was carried onto the next step without further purification.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Br:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:19][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: Cc1ccnc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccnc(C#N)c1Oc1cc(Cl)cc(Br)c1
Temperature: 70 °C

Procedure:
A mixture of 3-fluoro-4-methylpyridine-2-carbonitrile (2.1 g, 15.43 mmol), 3-bromo-5-chlorophenol (3.68 g, 17.74 mmol) and cesium carbonate (5.03 g, 15.43 mmol) in DMF (30 mL) was heated at 70° C. for 1 hour and then at 80° C. for another hour, after which the mixture was partitioned between water (300 mL) and ethyl acetate (2×500 mL). The combined extracts were washed with water (100 mL) and then brine (100 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The residue was chromatographed using RediSep column (330 g) and eluted with a gradient of 0-10% EtOAc/CH2Cl2 and the pure fractions combined and concentrated on the rotary evaporator to give the title compound. LRMS (M+1)=324.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[F:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: CCc1ccncc1
Product: CC(CCc1ccc(F)cc1)c1ccncc1
Yield: 77.9 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.90 g (9.35 mmol) of 4-fluorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.67 g of the desired compound (yield: 77.9%). The resulting compound was identified as 1-(4-fluorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 5) by the following analytical results.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.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]>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2cccc(Br)c2)C1
Temperature: 80 °C
Yield: 59.3 %

Procedure:
1,3-Dibromobenzene (0.2 g, 0.85 mmol), (R)-tert-butyl pyrrolidin-3-ylmethylcarbamate (0.17 g, 0.85 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), BINAP (40 mg, 0.06 mmol) and sodium tert-butoxide (98 mg, 1.02 mmol) were suspended in toluene (2 mL). The mixture was heated at 80° C. for 16 hr. The mixture was cooled and diluted with water and EtOAc. The organic layer was separated, passed through a phase separator cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl (1-(3-bromophenyl)pyrrolidin-3-yl)methylcarbamate as a yellow oil (0.179 g, 59%). This oil (0.179 g, 0.5 mmol) was suspended in 1,4-dioxane (2 mL). Bis-pinacolato-diboron (0.166 g, 0.66 mmol), potassium acetate (65 mg, 0.66 mmol) and Pd(dppf)Cl2 (20 mg, 0.025 mmol) were added and the mixture was heated at 100° C. for 16 h. The solution was cooled, diluted with DCM and filtered through celite. The solvent was removed under reduced pressure to afford crude (R)-tert-butyl (1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methylcarbamate as a brown oil. A mixture of this oil (0.5 mmol), tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.177 g, 0.44 mmol), Na2CO3 (0.7 mL, 2M aq. solution, 1.32 mmol) in DME (4.3 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (72 mg, 0.09 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 40 min. The solvents were removed under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to yield (R)-tert-butyl 2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a yellow oil (86 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.90 (s, 1H), 7.98 (s, 1H), 7.58 (s, 1H), 7.00 (s, 1H), 6.63-6.57 (m, 1H), 4.71-4.69 (m, 1H), 3.92 (s, 3H), 3.59-3.36 (m, 5H), 2.67-2.46 (m, 1H), 2.14-2.13 (m, 1H), 1.84-1.80 (m, 1H), 1.55 (s, 9H), 1.54 (s, 9H). Three protons not seen
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
A mixture of 2-Fluoro-5-Chloro Nitro benzene (0.5 g, 2.85 mmol), 4-Acetamidophenol (0.45 g, 3.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in DMSO (5 mL) was heated 6 hr at 90° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer washed with water, 20% aqueous potassium hydroxide solution and aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent concentrated under vacuum leaving the title compound as a tan solid (0.71 g, 81%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[O:23]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.7 %

Procedure:
To a solution of 6-(Boc-amino)hexylamine (4.95 g, 23 mmol) and Et3N (2 eq, 6.4 ml, 46 mmol) in 25 ml CH3CN was added dropwise 4-phenoxybenzenesulfonyl chloride solution (1 eq, 6.16 g, 23 mmol) in 15 ml CH3CN. The reaction was stirred for 2 days at room temperature. The precipitate was filtered and the solvent was evaporated. The residue was purified by silica gel chromatography [eluent: CH2Cl2/1-2% MeOH] to yield 6.68 g (64%) a colorless oil, which solidified to a white solid, m.p.=77-78° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[CH2:13][CH:12]2[CH3:30])[CH:5]=1.[Li+].[OH-]>C1COCC1>[CH3:30][CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([OH:29])([C:21]([F:24])([F:23])[F:22])[C:25]([F:27])([F:28])[F:26])[CH:15]=2)[N:11]1[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cccc(CN2c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3CC2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
A solution of 66 mg (0.118 mmol) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-benzoic acid methyl ester (example 61) in 0.5 mL of THF was treated with 0.2 mL of a 1M aqueous LiOH solution and stirred for 10 hrs at RT. The solvents were evaporated and the residue distributed between EtOAc and a aqueous solution of NH4Cl. Drying of the combined organic phases over Na2SO4 and evaporation of the solvent yielded 51 mg (99%) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-benzoic acid, light yellow gum, MS: 432 (M−H)−.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C(C)C)(C(C)C)[N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][C@H:33]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[CH:24]1)(C)C.C(=O)([O-])O.[Na+].C(OCC)C>O1CCCC1>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][C@H:33]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[CH:24]1
Reactant: CCCN[C@H](CCC)Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN[C@H](CCC)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 96.2 %

Procedure:
Tetra-n-butylammonium fluoride (9.64 g) was added to a solution of (R)-1-(1-triisopropylsilylindole-3-yl)-2-propylaminopentane (9.85 g) in tetrahydrofuran (45 mL) under stirring at room temperature and then stirred at room temperature for 50 minutes. A saturated aqueous sodium hydrogen carbonate solution (20 mL) and diethyl ether (40 mL) were added to the resulting solution. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography (NH-DM1020, AcOEt/Hexane=1/6). An aqueous 1 mol/L hydrochloric acid solution (100 mL) and diethyl ether (100 mL) were added to the resulting oil, and then the organic layer was extracted with an aqueous 1 mol/L hydrochloric acid solution. The aqueous layers were combined and washed with diethyl ether (30 mL). The aqueous layer was made basic with an aqueous 1 mol/L sodium hydroxide solution and extracted twice with diethyl ether (60 mL). The organic layers were combined and washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give (R)-1-(3-indolyl)-2-propylaminopentane (5.78 g, 96% yield) as a light orange oil.
Reaction SMILES: [CH:1]1([NH:7][CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C>[CH:1]1([N:7]([CH3:8])[CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
In DMF (50 ml) was dissolved N-cyclohexyl-N-methylamine (12.5, 0.11 mol), and to the solution were added potassium carbonate (27.6, 0.20 mol) and 4-nitrobenzylbromide (21.6, 0.10 mol). The mixture was stirred at room temperature for 5 hours. Under reduced pressure, the reaction mixture was concentrated. To the residue was added ethyl acetate, and the mixture was extracted with water. The ethyl acetate layer was washed with saturated sodium chloride solution, dried with MgSO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give N-cyclohexyl-N-methyl-N-(4-nitrobenzyl)amine (24.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][O:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:13])([CH3:11])[CH3:12]
Reactant: CI
Reactant: CC(C)(CO)c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a DMF (4 ml) solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropan-1-ol (199 mg, 0.8 mmol, WO2004074270A2) was added 60% sodium hydride (35 mg, 0.88 mmol) at 0° C. and the mixture was stirred at 0° C. for 15 minutes followed by additional stirring for 1 hour at room temperature. After the mixture was cooled to 0° C., methyliodide (342 mg, 2.4 mmol) was added and the mixture was stirred for 30 minutes at 0° C. followed by additional stirring for 16 hours at room temperature. Then, the reaction was quenched with water and the whole was extracted with EtOAc, which was dried over sodium sulfate. Then, filtration, evaporation and purification by silica gel column chromatography, eluting with hexane/EtOAc (20:1), gave the title compound (174 mg, 83% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[F:19])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:21]3[CH:22]=[C:23]4[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]4[C:25](=[O:27])[N:26]=3)=[CH:13][C:12]=2[F:19])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(Oc2ccc(CO)cc2F)ccc1Cl
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(Cl)c(C#N)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-chloro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.