Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:26][CH2:25][C:16]2([O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:30]([O:29][C:27]([C:14]1[CH:13]([S:10](=[O:12])(=[O:11])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[CH3:34])[CH2:26][CH2:25][C:16]2([O:17][C@H:18]([CH2:23][OH:24])[C@@H:19]([CH2:21][OH:22])[O:20]2)[CH:15]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)N(C)c1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
235 mg (0.49 mmol) of ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 17 was dissolved in 1.5 ml of acetone, and 84 mg (0.59 mmol) of methyl iodide and 138 mg (1.00 mmol) of potassium carbonate were added sequentially, followed by stirring for 3 hours at 50° C. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane ethyl acetate=1:3) to give 175 mg of the title compound as a white amorphous substance (yield: 73%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[CH2:10][C@@H:11]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][CH2:19]3)[O:12][C@@H:13]([CH2:14][NH:15]C=O)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:32][CH3:33].[OH-].[Na+]>Cl.CCO.O>[NH2:15][CH2:14][C@H:13]1[C:8]2[CH:7]=[CH:6][C:5]([O:32][CH3:33])=[C:4]([O:3][CH3:2])[C:9]=2[CH2:10][C@@H:11]([CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:23]2)[O:12]1
Reactant: COc1ccc2c(c1OC)C[C@@H](C1CCN(CCc3ccccc3)CC1)O[C@H]2CNC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1OC)C[C@@H](C1CCN(CCc3ccccc3)CC1)O[C@H]2CN

Procedure:
A mixture of cis-N-[3,4-dihydro-5,6-dimethoxy-3-[1-(2-phenylethyl)-4-piperidinyl]-1H-2-benzopyran-1-ylmethyl]formamide hydrochloride (4.7 g, 10 mmol) and its free base (2.1 g, 4.7 mmol) was dissolved in 3N HCl (30 ml)-EtOH (30 ml), and refluxed for 2 h. The reaction was diluted with water, and then stirred and cooled in an ice bath, while 50% aqueous NaOH was added dropwise. A white solid separated from solution and this was collected to afford the titled compound. The compound was recrystallized from toluene to afford the amine as a white solid, mp 100-102° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+].Cl>O>[C:1]1([C:7]2[N:11]=[CH:10][N:9]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCl
Reactant: c1ccc(-c2nc[nH]n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCn1cnc(-c2ccccc2)n1
Temperature: 115 °C
Reaction time: 66 h

Procedure:
A mixture of 3-phenyl-1H-1,2,4-triazole (1.46 g, 9.05 mmol), 3-chloropropionic acid (1.08 g, 9.96 mmol) and sodium hydroxide (2M, 9.05 mL, 18.1 mmol) in water (3 mL) was heated to 115° C. and stirred for 66 h. Another 0.5 equivalents of each 3-chloropropanoic acid and sodium hydroxide were added (pH increase to 11) and stirring was continued for another 24 h. Hydrochloric acid (2M, 10 mL) was added, the suspension was filtered and extracted with dichloromethane. The product was obtained after purification by supercritical fluid chromatography as light brown solid (236 mg, 1.09 mmol, 12.0%). MS: M=218.1 (M+H)+
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:34])[CH:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[C:26]([F:34])[CH:25]=2)[CH3:22])=[CH:14][C:15]=1[F:20]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (145 mg, 0.29 mmol) in CH3CN (2 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (0.06 ml, 0.44 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (3 ml) and zinc dust (60 mg) was added portion wise over 3 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4, concentrated under vacuo to afford 80 mg (67%) of the tile compound as a colorless oil. ES-MS m/e: 405.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2O.O=P(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[Cl:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl

Procedure:
To a stirred solution of the crude 6-methoxy-4-hydroxy-3-ethoxycarbonylquinoline (Step A, 74 g, 0.25 M) in dry toluene (300 mL) was added POCl3 (46.6 mL, 0.5 mol) followed by PCl5 (26 g, 0.125 mol). The mixture was heated at reflux for 6 h. The toluene and the excess of POCl3 were removed under vacuum. The solid residue was suspended into a mixture of 1N NaOH and ice. The resulting solid was filtered off, washed several times with water, then with a minimum amount of MeOH, and dried over P2O5 to give 6-methoxy-4-chloro-3-ethoxycarbonylquinoline as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:17])[C:13](=O)[CH2:14][CH3:15].B.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCC(=O)N(C)c1cc([N+](=O)[O-])ccc1OC
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCN(C)c1cc([N+](=O)[O-])ccc1OC
Yield: 96.6 %

Procedure:
N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) (10.0 g 42 mmol) and borane-methyl sulfide complex (21 mL of 2.0M solution in tetrahydrofurane) in 50 mL THF were heated unter reflux for 30 min, cooled and quenched by ice-water (slowly). Extraction with EtOAc and the organic layer washed with brine dried (Na2SO4), filtered and evaporated in vacuo to give (9.1 g, 96%) (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][N:3]=1.CC1C=C(O)C=CC=1C.[CH3:21][O:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])=[CH:25][CH:24]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:37][C:30]1([C:8]2[C:9]([OH:11])=[CH:10][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]=2)[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:40][CH:39]=2)[C:29]1=[O:38]
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Reactant: Cc1noc2cc(O)ccc12
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COc1ccc(CN2C(=O)C(O)(c3cc4c(C)noc4cc3O)c3ccccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 3-methylbenzo[d]isoxazol-6-ol (Iranpoor, N., et al., Tetrahedron Lett. (2006), 47:8247) to replace 3,4-dimethylphenol, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one was obtained (76%): mp 199-201° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.52 (d, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.18-7.13 (m, 1H), 7.05-7.03 (m, 1H), 6.89-6.75 (m, 5H), 4.83 (AB, 2H), 3.71 (s, 3H), 2.77 (s, 3H); MS (ES+) m/z 417.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:35][OH:36].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([C:22](=[N:35][OH:36])[NH2:23])[CH:24]=[CH:25][CH:26]=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NO
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(N)=NO)c2)C1

Procedure:
The mixture of 240 mg (0.45 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzonitrile, 47.2 mg (0.68 mmol) of hydroxylamine hydrochloride, 0.124 mL (0.9 mmol) of triethylamine, and 5 mL of ethanol was heated to reflux for 4 h. The solution was concentrated and the residue was poured into 20 mL of CH2Cl2 and 5 mL of aq NaHCO3 (PH>7). The aqueous layer was extracted with two 10 mL portions of CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated to afford the title compound as a white solid; Mass Spectrum: m/e=562 (M+1, 35Cl), 564 (M+1, 37Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=[CH:4][C:5]=4[CH3:24])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(C)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (72.6 mg, 0.224 mmol) in tetrahydrofuran (4.0 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (46.3 mg, 0.29 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (68 mg, 0.672 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, washed with ethyl acetate/hexane to give the title compound (64 mg, 64%) as a brown powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:11])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 2-fluoronitrobenzene (1.0 g, 7.09 mmol) in DMF (5 mL) were added H-ALA-OTBU HCl (2.6 g, 14.2 mmol) and DIPEA (2.5 mL, 14.2 mmol). The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated to afford 1.8 g (95%) of the desired product as orange oil. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](OC)=[O:17])=[C:12]([CH:20]([CH3:22])[CH3:21])[N:11]=[C:10]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])[N:9]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14]/[CH:15]=[CH:16]/[OH:17])=[C:12]([CH:20]([CH3:22])[CH3:21])[N:11]=[C:10]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C/C=C/O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Methyl (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)pyrimidin-5-yl]-1-propenoate (5.4 g) obtained in step I above was dissolved in toluene (30 ml) and the resulting solution was cooled to −78° C. To this solution, diisobutylaluminium hydride (20% solution in toluene, 45.2 ml) was added and the reaction mass was stirred at −70° C. for 15 min. Thereafter, reaction mass was poured into aqueous hydrochloric acid (1N, 30 ml). The organic layer was separated and washed with water (20 ml). The solvent was distilled under reduced pressure to yield pure (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propen-1-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:10][C:11]1[N:15]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:14]=[N:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl.Cl.C(OCC)C>[CH3:1][C:2]1([CH3:8])[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:10][C:11]1[N:15]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:14]=[N:13][N:12]=1
Reactant: CC1(C)COCCN1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)COCCN1Cc1nnnn1-c1ccc(C#N)cc1

Procedure:
A solution of 3,3-dimethylmorpholine (49.7 mg, 0.328 mmol, commercially available, for example from Otava, Kiev, Ukraine or Tyger Scientific, Ewing, USA), 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (60 mg, 0.273 mmol, may be prepared as described in Intermediate 10) and di-isopropylethylamine (0.110 mL, 0.628 mmol) in acetonitrile (0.7 mL) was heated to 120° C. for 30 minutes in a microwave reactor. The reaction mixture was allowed to cool and the solution purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The residue was partitioned between saturated NaHCO3 (aq, 2 mL) and DCM (5 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was dissolved in a minimum of dichloromethane before the addition of 1N HCl in diethyl ether (1 mL). The compound was partitioned between saturated NaHCO3 (aq, 2 mL) and DCM (5 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The crude product was further purified by silica chromatography (Biotage SP4, eluting 20% EtOAc in iso-hexane (3 column volumes) then a gradient from 20-60% EtOAc in iso-hexane (over 12 column volumes)) to yield a colourless gum. The residue was dissolved in a minimum of dichloromethane before the addition of 1N HCl in diethyl ether (1 mL). The solvent was removed under vacuum to yield a pale yellow solid which was triturated with methanol (0.5 mL) then dried under vacuum to yield the title compound as a white solid (22 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[O:13]([CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([CH2:21][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:23]=1)=[O:8]
Reactant: O=C(Cl)c1cccc(CCCl)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CNC(=O)c2cccc(CCCl)c2)c1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A solution of 3-(2-chloroethyl)benzoyl chloride (2.43 g, 12.0 mmol) in ethyl acetate (10 mL) was added to a solution of 3-(tert-butyldimethylsiloxymethyl)benzylamine (3.01 g, 12.0 mmol) and triethylamine (3.3 mL, 24 mmol) in ethyl acetate (20 mL) at 0° C., and the resulting mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with a 5% aqueous potassium hydrogensulfate solution, water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 200 mL; hexane/ethyl acetate=10/1 to 3/1) to obtain the title compound (3.74 g, 75%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C@@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27]Cl.Cl.ClCC(=N)OCC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([C@@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[C:27]([CH2:26][Cl:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: ClCCCl
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2cc(Br)ccc12
Agent: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3cc(Br)ccc3c21
Temperature: 70 °C

Procedure:
A 1-L, three-necked, Morton flask, equipped with overhead stirrer, was charged with 7-bromo-N4-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)quinoline-3,4-diamine (33.4 g, 81.0 mmol) and 1,2-dichloroethane (400 mL) and the mixture was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (29.1 g, 184.0 mmol) was then added in portions and the reaction mixture was heated to 70° C. for 3 days. The reaction mixture was then cooled to ambient temperature and treated with CHCl3 (500 mL) and saturated aqueous NaHCO3 solution (700 mL). The layers were separated and the organic portion was concentrated under reduced pressure to give 38 g of 7-bromo-1-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline as a golden solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17][CH2:18][C:19]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH:22]=2)=[O:20])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:16][CH2:17][CH2:18][C:19]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:22]=2)=[O:20])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(OCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC(OCCC(=O)c1cn(CCCC(=O)O)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-[3-[1-(4-isobutylphenyl)pentyloxy]propionyl]-1-indolyl]butyrate obtained in Ex. 34 was used in place of ethyl 4-[3-[8(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-[3-[3-[1-(4-isobutylphenyl)pentyloxy]propionyl]-1-indolyl]butyric acid as an oil.
Reaction SMILES: [CH2:1]([O:5][CH3:6])[C@H:2]1[O:4][CH2:3]1.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]([CH2:3][C@H:2]([OH:4])[CH2:1][O:5][CH3:6])[CH2:3][C@H:2]([OH:4])[CH2:1][O:5][CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC[C@@H]1CO1
Reactant: NCc1ccccc1
Solvent: CO
Product: COC[C@@H](O)CN(Cc1ccccc1)C[C@H](O)COC
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A solution of (S)-methyl glycidyl ether (10 g) and benzylamine (3.62 g) in methanol (50 ml) was stirred at 55° C. for 2 hours. To the mixture was added (S)-methyl glycidyl ether (1 g), and the mixture was stirred at 55° C. for 2 hours, and then evaporated under reduced pressure. Toluene was added to the residue and evaporated under reduced pressure to give (2S)-1-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-3-methoxypropan-2-ol (8.84 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)ccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,5-dimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=589.7)=85%.
Reaction SMILES: [NH3:1].C(=O)=O.[NH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][CH:7]=[N:6]1.CCOCC>C(Cl)Cl.CCO.CC(O)=O>[NH2:1][C:7]1[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:5][N:6]=1
Reactant: C1=Cc2ccccc2NN=C1
Reactant: N
Agent: O=C=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: NC1=NNc2ccccc2C=C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Ammonia (500 mL) was condensed with a dry ice condensor and maintained at −78° C. To this was added a solution of 6 (35 g, 91 mmol) in CH2Cl2 (600 mL). After 8 h, the dry ice condensor was removed and the reaction was warmed to room temperature allowing the ammonia to evaporate. The remaining solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a white solid. This solid was dissolved in EtOH (500 mL) and AcOH (15 mL), and the resulting solution was refluxed for 24 h, and concentrated to yield a yellow-red oil. Addition of Et2O (300 mL) to this oil resulted in the precipitation of 8 (13 g, 47%) as a white powder: 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1 H), 7.83-7.05 (m, 8 H), 4.39 (s, 2 H); ESI MS m/z=305 [C15H11F3N2O+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:36])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[N:27]=[C:28]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)[S:29][CH:30]=3)[CH2:23][C:22](=[O:36])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2csc(-n3ccnc3)n2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K91) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (46 mg).