Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1

Procedure:
(4RS,5SR)-5-(4-Fluorophenyl)-4-[4-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (18.75 g, 55.26 mmol) and sodium hydroxide (8.84 g, 221 mmol) were heated under reflux in ethanol (100 ml)-water (10 ml) for 5 hrs. The reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic-layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane/ethyl acetate=1/1-ethyl acetate) and crystallized from diethyl ether-hexane to give the objective substance.
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[CH2:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:12]1[O:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Si:16]([O:15][CH2:11][C@H:12]([OH:14])[CH:13]=[CH2:1])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CO1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (58.2 mL, 2.64 M solution in hexane) was added dropwise to a suspension of trimethylsulfonium iodide (32.4 g) in tetrahydrofuran (400 mL) in a nitrogen atmosphere at −20° C. The reaction solution was stirred at the same temperature for 30 minutes. tert-Butyldimethylsilyl (R)-(−)-glycidyl ether (10 g) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred for three hours with gradual heating to room temperature. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride twice. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (9.6 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.Cl[C:20]1[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:20]4[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Reactant: O=Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-ol (9-5, 35 mg, 0.14 mmol, 1 equiv.) and 2-chloropyridine-3-carbaldehyde (29 mg, 0.20 mmol, 1.5 equiv.) were dissolved in N,N-dimethylacetamide (1.5 mL) and treated with cesium carbonate (89 mg, 0.27 mmol, 2 equiv.). The mixture was irradiated at 100° C. in a microwave reactor for 30 minutes, cooled to ambient temperature and poured into water (30 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound 417.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:23].CCN(CC)CC.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: Cc1ccc(Cn2c(OS(=O)(=O)C(F)(F)F)cc3ccccc3c2=O)c(C)c1
Reactant: C#CC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2c(C#CC(C)(C)O)cc3ccccc3c2=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of trifluoromethanesulfonic acid 2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydro-isoquinolin-3-yl ester (50 mg, 0.12 mmol) in THF (1.5 mL) was added Et3N (83 μL, 0.59 mmol). The resulting mixture was then degassed by bubbling argon through the solution for twenty minutes. The degassed solution was then treated with 2-methyl-but-3-yn-2-ol (23 μL, 0.24 mmol) followed by tetrakistriphenylphosphine Pd(0) (13 mg, 12 μmol) and Cul (˜2 mg, ˜12 μmol). The resulting suspension was stirred at ambient temperature for 16 hours, then filtered through a short plug of silica gel eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 50% ethyl acetate/hexane on a silica column. The product peak was collected to afford 2-(2,4-dimethylbenzyl)-3-(3-hydroxy-3-methylbut-1-ynyl)-2H-isoquinolin-1-one (27 mg, 65% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.43 (1H, d, J=8.1 Hz), 7.70-7.64 (1H, m), 7.75-7.49 (2H, m), 7.0 (1H, s), 6.89-6.85 (2H, m), 6.65-6.61 (1H, m), 5.42 (2H, s), 2.40 (3H, s), 2.26 (3H, s), 1.40 (6H, s). ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[OH:10])[CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:36])[CH3:35].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([N:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:34](=[O:36])[CH3:35])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[OH:10])[CH:5]=[CH:4][N:3]=1
Reactant: OC(c1cccc(C(F)(F)F)c1)C(NC1CCCC1)c1ccnc(F)c1
Reactant: CC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N(C1CCCC1)C(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2-(2-fluoro-pyridin-4-yl)-2-cyclopentylamino-1-(3-trifluoromethyl-phenyl)-ethanol (6) (1.0 g, 2.7 mmol) and diisopropylamine (0.95 mL, 5.4 mmol) in methylene chloride (10 mL) was placed under argon and cooled to −10° C. Acetyl chloride (0.21 mL, 3.0 mmol) in methylene chloride (1.0 mL) was slowly added to the reaction mixture. After 2 hrs, ethyl acetate was added (200 mL) followed by aqueous citric acid (50 mL of a 10% solution). The organic layer was then washed with aqueous sodium bicarbonate (50 mL of a sat. solution) and water (50 mL), dried (sodium sulfate), filtered, and concentrated. The crude residue was passed though a pad a silica gel (50% ethyl acetate in hexane) to remove minor impurities, and taken to the next step. Colorless oil (95%): 1H NMR (300 MHz, CDCl3) d 8.54 (d, J=5.1 Hz, 1 H, Pyr), 7.49 (m, 4 H, Ar), 6.81 (d, J=5.0 Hz, 1 H, Pyr), 6.72 (s, 1 H, Pyr), 5.63 (s, 1 H, OH), 5.46 (s, 1 H, PhCHOH), 4.34 (s, 1 H, CHCHN), 4.16 (m, 1 H, CH2CHCH2), 2.32 (s, 3 H, COCH3), 1.90 (m, 1 H, CH2), 1.60 (m, 7 H, CH2).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:34](=[O:35])[N:15]2[CH:16]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12.F[C:37]1[NH:38][CH:39]=[CH:40][N:41]=1>C(#N)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:19][C:17]1([CH3:20])[CH:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[N:15]2[C:34](=[O:35])[CH:13]([NH:12][C:37]3[NH:38][CH:39]=[CH:40][N:41]=3)[C@H:14]2[S:18]1
Reactant: Fc1ncc[nH]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC1(C)S[C@@H]2C(Nc3ncc[nH]3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
A mixture of p-nitrobenzyl 6-amino-2,2-dimethylpenam-3-carboxylate toluene-p-sulphonate (523 mg.) and 2-fluoroimidazole (100 mg.) in acetonitrile (2 ml.) was stirred at 50° for 3 hours. The resulting solution was evaporated to dryness and the residue obtained was triturated with ether to give p-nitrobenzyl 2,2-dimethyl-6-(imidazol-2-yl)aminopenam-3-carboxylate toluene-p-sulphonate as a 50% pure solid (572 mg.) which was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)C.CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1
Reactant: OCC#Cc1cccc2ccncc12
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Solvent: CO
Product: OCCCc1cccc2ccncc12
Reaction time: 22 h
Yield: 33.3 %

Procedure:
A solution of 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol in a mixture of 10 mL of ethanol and 5 mL of methanol was hydrogenated over 0.06 g 10% Pd/C at room temperature and atmospheric pressure for 22 hours and then at 50 Psi for 20 hours. After the catalyst was removed by filtration and the filtrate was concentrated, the residual oil was purified by HPLC (methanol-chloroform; 1:19) and crystallized from ethyl acetate-hexane to yield 0.136 g of 8-isoquinolinepropanol, mp 66°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[C:33]([O:36][CH3:37])[S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].CO.C1COCC1.[OH-].[Li+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[C:33]([O:36][CH3:37])[S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(OC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCOc2ccc(-c3csc(OC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Reaction time: 2.75 h
Yield: 97.2 %

Procedure:
The compound of Example 23 (20 mg, 35.1 μmol) was added to 2 mL of 4:1 methanol/THF and 0.08 mL of 1 N lithium hydroxide, and the reaction was allowed to proceed at room temperature for 2.75 hr. The mixture was poured into ethyl acetate/water, and the ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated to give the product (19 mg, 34.1 μmol, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (43 mg, 33%). MS (ISN) 509.0 [(M−H)−]; mp 273-274° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][CH3:15]>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A solution of 4-fluorobenzenesulfonyl chloride (1.95 g, 10 mmol) and dimethylamine hydrochloric acid salt (978 mg, 12 mmol) in tetrahydrofuran (10 mL) was added to a solution of 4-dimethylaminopyridine (3.05 g, 25 mmol) in tetrahydrofuran (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by flash column (elution with 20% ethyl acetate in petroleum ether) to afford 4-fluoro-N,N-dimethyl-benzenesulfonamide (1.02 g, 50%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14][N:25]=[N+:26]=[N-:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](CCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCN=[N+]=[N-])N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 101.1 %

Procedure:
To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-bromopropyl]benzenesulfonamide (1.64 g, 3.27 mmol) in THF/H2O (20/4, 24 mL) was added sodium azide (2.13 g, 32.7 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was extracted with ether (3×60 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 1.38 g of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzenesulfonamide as a colorless oil in 95% yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:14]=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred solution of 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238) (17.0 g, 70.24 mmol) in methanol (200 mL), was added NaBH4 (5.33 g, 140.5 mmol) portion-wise at 0° C. The reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction, the solvent was concentrated and the crude product was diluted with water and extracted with ethyl acetate (2×300 mL). The organic part was dried over Na2SO4 and evaporated to give [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-methanol (239) (15 g, 90%) as a white solid which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1CC#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: N#CCc1cccc(Cl)c1OCC(F)(F)F
Agent: Cl
Product: O=C(O)Cc1cccc(Cl)c1OCC(F)(F)F

Procedure:
2-(2,2,2-trifluoroethoxy)-3-chlorophenyl-acetonitrile (1.2 g, 5.1 mmol) from Step 3 above was refluxed in a 2:1 mixture of acetic acid and concentrated aqueous HCl (25 mL) for 12 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetic acid as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{[3-Bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-tert-butoxycarbonylamino-propionic acid methyl ester (0.142 g, 0.26 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:30])[N:24]([CH3:29])[C:25](O)=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:31].CN(C)C1C=CC=CC=1.[Cl-:41]>O=P(Cl)(Cl)Cl>[Cl:41][C:25]1[N:24]([CH3:29])[C:23](=[O:30])[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([F:31])[CH:18]=2)=[CH:27][N:26]=1
Reactant: [Cl-]
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(O)n(C)c4=O)cc3F)c2cc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Cl)n(C)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-hydroxy-3-methyl-3H-pyrimidin-4-one (Step 2, 678.8 mg, 1.605 mmol) was dissolved in POCl3 (16 mL) and N,N-dimethylaniline (1.6 ml) and heated at 125° C. for 8.5 h then cooled to RT and stirred overnight. The reaction was concentrated, diluted with CH2Cl2 (125 mL) and washed with saturated NaHCO3 (25 mL, 17 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Because of the propensity of title compound to hydrolysis, the crude chloride was used for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:4]=[CH:5][N:6]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19]>C1COCC1>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31]([NH:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:4]=[CH:5][N:6]=1)=[O:32])[CH3:19]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCn1ncnc1N
Solvent: C1CCOC1
Product: CCCCCCCCCCCn1ncnc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Yield: 37.7 %

Procedure:
A solution of 3-amino-2-undecyl-1,2,4-triazole (3.0 g, 12.6 mmol) and 2,6-diisopropylphenyl isocyanate (3.9 mL, 19.2 mmol) in THF (100 mL) was heated under reflux (40 hours). The resulting solution was cooled (25° C.) and concentrated in vacuo. The resulting oil was triturated with hexane and the resulting solid was collected by filtration and recrystallized from hot hexane to yield 2.1 g (37.8%) of the title compound as a white solid; mp 146.5°-147.5° C.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].C([O:17][C:18]1[N:23]=[C:22]2[NH:24][CH:25]=[N:26][C:21]2=[CH:20][CH:19]=1)C1C=CC=CC=1>>[OH:17][C:18]1[N:23]=[C:22]2[N:24]([CH:2]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[O:9])[CH:25]=[N:26][C:21]2=[CH:20][CH:19]=1
Reactant: O=C1CCCCCC1Cl
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: O=C1CCCCCC1n1cnc2ccc(O)nc21

Procedure:
From 2-chlorocycloheptanone and 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine, prepared in a similar manner as the one described in Example 1.11, the title compound was obtained. LCMS m/z=246.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.50 (m, 1H), 1.70-2.10 (m, 5H), 2.25-2.40 (m, 2H), 2.55-2.65 (m, 1H), 2.75-2.85 (m, 1H), 5.67 (dd, J1=9.5 Hz, J2=4.3 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.88 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ncccn2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncccn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 135 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A suspension of 4-(pyrimidin-2-ylmethoxy)pyridin-2(1H)-one (242 mg, 1.19 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (522 mg, 1.43 mmol), CuI (272 mg, 1.43 mmol), 8-hydroxyquinoline (35 mg, 0.24 mmol) and Cs2CO3 (426 mg, 1.31 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135° C. with stirring overnight. The suspension was cooled, 40:9:1 CH2Cl2/MeOH/NH4OH (50 mL) was added, and the resulting suspension was stirred at 25° C. for 1 h. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) yielded the title compound (256 mg, 44%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J=4.5 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.31-7.27 (m, 3H), 7.01 (br d, J=8.0 Hz, 1H), 6.17 (dd, J=7.5, 2.8 Hz, 1H), 6.00 (d, J=2.8 Hz, 1H), 5.32 (s, 2H), 4.64 (br s, 2H), 3.88-3.79 (m, 2H), 3.62 (s, 3H), 2.84-2.78 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.CN(C)C=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: C1CCNCC1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccc(C)cc3)c2c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
240 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.75 ml of piperidine, and the mixture was stirred for 7.5 hours at 110° C. Another 0.75 ml of piperidine was added, and it was heated for another 4 hours at 110° C. It was mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 16 mg was obtained.