Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21]>C1COCC1.C(Cl)Cl>[NH2:17][C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)ccnc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc4c3c(N)nn4C)cc2)c1
Yield: 46.2 %

Procedure:
A solution of Example 40 (87 mg, 0.36 mml) and 1-isocyanato-3-methylbenzene (0.046 mL, 0.36 mmol) in THF (3 mL), CH2Cl2 (3 mL) was stirred at room temperature for 5 h. The resulting precipitate was filtered off and purified via HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 20% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 ml/min over 50 min, to give the 62 mg of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 3.83 (s, 3H) 6.81 (d, J=7.46 Hz, 1H) 6.92 (d, J=4.75 Hz, 1H) 7.17 (t, J=7.80 Hz, 1H) 7.26 (d, J=8.48 Hz, 1H) 7.32 (s, 1H) 7.53 (d, J=8.81 Hz, 2H) 7.65 (d, J=8.82 Hz, 2H) 8.40 (d, J=4.75 Hz, 1H) 8.67 (s, 1H) 8.90 (s, 1H). MS (ESI(+)) m/e 373 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C1N2CCN(CC2)C1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([Br:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C1(C)C=CC=CC=1>[Br:33][C:32]1[CH:34]=[CH:35][C:29]([S:26]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.15 g, 8.76 mmol) and DABCO (1.57 g, 14.0 mmol) in PhMe (10 mL) at RT was added a solution of brosyl chloride (3.14 g, 12.3 mmol) in PhMe (5 mL). A white precipitate formed, the reaction mixture was stirred for 20 minutes and filtered. The filtrate was partitioned between EtOAc and saturated aqueous NaHCO3; the layers separated; and the organic phase washed with 1 M HCl, water and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil (4.0 g), which was used without further purification. LRMS (M+Na)+ Calcd.: 488; found 488.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccncc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(2-fluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.56 (6H, s), 7.69 (1H, dd, J 8 and 8), 7.84-7.92 (2H, m), 7.99-8.04 (1H, m), 8.21 (2H, d, J 6), 8.53 (1H, s), 8.98 (2H, d, J 6),9.30 (1H, dd, J 7 and 3); m/z (ES+) 349 (M++H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30]([O:32]CC)=[O:31])=[N:25]1)=[O:14].O.[OH-].[Li+]>C1COCC1.O>[OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[N:25]1)=[O:14]
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)nn1-c1ccc([N+](=O)[O-])cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of (S)-ethyl 1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxylate (18.0 g, 38.8 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide monohydrate (5.0 g, 116.8 mmol) followed by stirring at RT for 6 h. The reaction mixture was concentrated invacuo, diluted with water (80 mL) and extracted with diethyl ether (100 mL). The aq. layer was cooled to 0° C., acidified up to pH ˜4 using 3N HCl and extracted with EtOAc (200 mL×2) twice. The combined organic layers were washed with water (200 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a white colored solid 14 g (82%). Rf=0.25 (70% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 12.90-12.50 (brs, 1H), 8.64-8.30 (m, 2H), 8.06-7.72 (m, 1H), 7.24-6.82 (m, 4H), 6.80-6.42 (m, 1H), 5.20-3.80 (m, 6H), 3.40-2.40 (m, 2H), 2.40-2.10 (m, 3H); ES-MS: m/z 437.2 (M+H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][C:15]([O:17]CC)=[O:16])[O:9][CH2:8][CH2:7]2>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[O:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)CC1OCCc2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1OCCc2cc(Br)ccc21

Procedure:
Sodium hydroxide (1N, 19.8 ml) is added to ethyl (6-bromoisochroman-1-yl)acetate (LXXVII, 3.96 g, 13.2 mmol) in ethanol (20 ml). The mixture is stirred for 2 hr, at which time the ethanol is removed under reduced pressure. The residue is acidified with hydrochloric acid (4N, approximately 6 ml) and extracted with ether. The organic phase is separated and is washed with dilute aqueous hydrochloric acid, dilute aqueous hydrochloric acid/saline, and saline, dried over magnesium sulfate, and concentrated under reduced pressure. The (6-bromoisochroman-1-yl)acetic acid (LXVIII) thus obtained is stirred at 0° with THF (20 ml) and borane-methyl sulfide (3.75 ml, 39.6 mmol) is added over several minutes. After stirring at 0° for 3.5 hr, the mixture is allowed to slowly warm to 20-25° and methanol is added to quench excess borane, until no further gas evolution is observed. The mixture is then concentrated under reduced pressure and methanol is again added and removed under reduced pressure. This procedure is repeated twice and the residue is then partitioned between dichloromethane, aqueous sodium bicarbonate and saline. The organic phase is separated, dried over sodium sulfate and concentrated to give 2-(6-bromoisochroman-1-yl)ethanol (LXXIX), NMR (CDCl3) 2.04, 2.21, 2.65, 3.02, 3.70-3.87, 4.17, 4.92, 6.93 and 7.28 δ.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[NH2:6][C:7]1[CH:15]=[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[N:8]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:6][C:7]1[C:15]([Cl:4])=[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[N:8]=1
Reactant: Nc1cc2n(n1)CCCC2
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nn2c(c1Cl)CCCC2
Reaction time: 1 h

Procedure:
5 g (37 mmol) sulfuryl chloride was added dropwise to 5.08 g (37 mmol) 2-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, dissolved in 30 ml methylene chloride, with ice-cooling. The mixture was stirred for 1 hour, then added to saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. Purification was carried out by silica gel column chromatography to ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>CN(C=O)C>[CH2:19]([NH:21][C:22]([NH:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:18])[N:14]=1)=[O:23])[CH3:20]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 85 °C

Procedure:
A mixture of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (0.40 g, 1.4 mmol) and ethyl isocyanate (0.121 ml, 1.5 mmol) in dry DMF (3 ml) is heated at 85° C. for 1 hour. The solvent is removed and the product is purified by chromatography on silica eluting with hexane-ethyl acetate (1:1) to give the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:26]([OH:28])[CH3:27]>>[CH2:26]([O:28][C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:27]
Reactant: Fc1ccc(-c2c(-c3cccc(Cl)n3)nn3ccccc23)cc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Add sodium hydride (20.7 mg, 0.52 mmol) to a solution of 2-(6-chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (33.5 mg, 0.10 mmol) in ethanol (2.5 mL) at 0° C. Stir the reaction mixture at 0° C. for 30 minutes and at 80° C. for 48 hours. Cool the reaction mixture to room temperature and concentrate in vacuo Using the same procedure as above afforded the title compound 31 mg (93%) as an off-white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:12]=[CH:13][CH:14]=1>>[CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCC(C=O)CC
Reactant: Nc1cccc(/C=C/CNC(=O)C(F)(F)F)c1
Product: CCC(CC)CNc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Hydrogenation of 2-ethylbutanal and (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide following the method used in Example 31 gave N-(3-(3-(2-ethylbutylamino)phenyl)propyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.5 g, 90%); 1H NMR (400 MHz, DMSO-d6) δ 9.42 (bs, 1H), 6.94 (t, J=7.2 Hz, 1H), 6.38-6.37 (m, 2H), 6.32 (d, J=7.2 Hz, 1H), 5.40 (t, J=5.6 Hz, 1H), 3.21-3.16 (m, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.77-1.70 (m, 2H), 1.48-1.41 (m, 1H), 1.39-1.31 (m, 4H), 0.85 (t, J=7.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][CH:10]([CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:29](O)[CH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH:10]([CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([O:13][CH2:29][CH3:30])=[O:12])=[O:8])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)NC(Cc2cc3ccccc3[nH]c2=O)C(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(Cc1cc2ccccc2[nH]c1=O)NC(=O)c1ccc(OC)cc1

Procedure:
1.8 Grams of 2-(4-methoxybenzoyl)amino-3-(2-quinolon-3yl)propionic acid was dissolved in 100 ml of ethanol, then to this solution was introduced and saturated with hydrogen chloride gas under an ice-cooled condition with stirring. The reaction mixture was then refluxed for 5 hours and after completion of the reaction, the solvent was removed by distillation under a reduced pressure, the residue obtained was recrystallized from ethyl acetate-ethanol to obtain 1.5 g of ethyl 2-(4-methoxybenzoyl)amino-3-(2-quinolon-3-yl)propionate in the form of white powder product.
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:22][Mg]Br>C1COCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:20])[CH3:22])=[CH:8][CH:9]=1
Reactant: CON(C)C(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous THF (200 mL) at 0° C. was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol). After stirring at 0° C. for 2 h, the reaction was quenched with MeOH (5 mL) and 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between saturated ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated, and the aqueous layer was extracted with ether (2×200 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, 1H), 3.34 (dd, 1H), 2.90 (dd, 1H), 2.03 (s, 3H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([F:19])=[C:6]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1.S(OC)(O[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[Cl:3][C:4]1[C:5]([F:19])=[C:6]([N:10]([CH3:24])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(Nc1cccc(Cl)c1F)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccccc1)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Into toluene (60 g) were added 85% potassium hydroxide (2.8 g, 0.05 mol) and 10.0 g (0.40 mol) of N-(3-chloro-2-fluorophenyl)benzamide obtained above. While the reaction mixture was heated at reflux, 6.1 g (0.05 mol) of dimethyl sulfate was added dropwise. The reaction was conducted with a dean stark trap to remove the water generated. After the dropwise addition was completed, the mixture was stirred for 1 hour and allowed to cool to room temperature. The resultant was mixed with 20 g of a 5% aqueous sodium hydroxide solution and stirred for 1 hour. The mixture was allowed to separate to give a toluene layer, which was washed with 40 g of water. The toluene layer was concentrated under reduced pressure, and the resultant residue was washed with n-hexane to obtain 9.97 g of the title compound (yield: 94%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30].C(N(CC)CC)C>>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH:31][S:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:13])=[O:12])[CH3:30]
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c(OC)c1
Yield: 69.2 %

Procedure:
The title compound was prepared from 2,4-dimethoxybenzenesulfonyl chloride (473 mg, 2.0 mmol), 1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethylamine (466 mg, 2.0 mmol), and triethylamine (334 μL, 2.2 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40Mi column of prepacked column of silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (600 mg, 69%) as a white solid;
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])=[CH:13][CH:14]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1
Yield: 104.6 %

Procedure:
Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed with continuous water separation for 8 hours. The mixture was cooled and washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl 4-hydroxyphenylacetate. That compound can be represented by the formula: ##STR24##
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:25]=1)#[N:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 64.3 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 528 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane at room temperature. After 2 hours at room temperature the mixture was washed with sodium bicarbonate solution and the organic phase was dried over sodium sulphate and evaporated. The residue crystallized from t-butyl methyl ether and was recrystallized from toluene to give 360 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 158°-160° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 79.5 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 10 mL of methyl ethyl ketone. The resulting mixture was refluxed under stirring at 77-82° C. in an argon gas atmosphere for 2 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.36 g (reaction yield: 95.4%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[F:18][C:19]([F:31])([F:30])[S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([S:20][C:19]([F:31])([F:18])[F:30])=[CH:22][CH:23]=3)[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(SC(F)(F)F)cc3)cc(-c3ccccc3)n2n1
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A solution of 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 62 mg, 0.276 mmol) and pyridine (0.69 mL) in a 20 mL scintillation vial was cooled to 0° C. then treated with 4-(trifluoromethylthio)benzoyl chloride (100 mg, 0.415 mmol). The reaction mixture was stirred for 2 h, partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer subsequently washed with water and then brine. The organic layer was then dried over sodium sulfate, filtered, concentrated under reduced pressure, diluted with methanol, filtered, and purified via preparative HPLC (80-80% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (58.8 mg, 50%). Melting point (100.9-101.6° C.). 1H NMR (DMSO-d6) δ: 11.49 (s, 1H), 8.15 (d, J=8.6 Hz, 2H), 8.06 (dd, J=6.7, 2.9 Hz, 2H), 7.93 (s, 1H), 7.87 (d, J=8.3 Hz, 2H), 7.56-7.66 (m, 3H), 6.41 (s, 1H), 2.40 (s, 3H); ESI-MS: m/z 429.1 (M+H)+. Melting point (100.9-101.6° C.).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:24])([F:23])[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]O>O1CCOCC1.C(OCC)(=O)C>[F:5][C:6]([F:24])([F:23])[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:2]
Reactant: OCc1ccccc1Oc1cccc(OC(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1cccc(Oc2ccccc2CBr)c1
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
Phosphorus tribromide (5 ml, 53 mmol) was added to a solution of [2-(3-(trifluoromethoxy)phenoxy)phenyl]methanol (5.33 g, 18.9 mmol) in dioxane (100 ml). The reaction mixture was stirred for 1.5 hours. Another portion of phosphorus tribromide (5 ml, 53 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was diluted with ethyl acetate (500 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (300 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified on silica (200 g), using ethyl acetate/heptane (1:4) as eluent, to give 2.13 g of 2-(3-(trifluoromethoxy)phenoxy)benzyl bromide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:48][C:49]([F:62])([F:61])[C:50]1[NH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([CH2:59][NH2:60])=[CH:54][CH:53]=2>C(#N)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[N:7][C:6]([C:9]([NH:60][CH2:59][C:55]2[CH:56]=[C:57]3[C:52](=[CH:53][CH:54]=2)[NH:51][C:50]([C:49]([F:62])([F:48])[F:61])=[CH:58]3)=[O:11])=[CH:5][CH:4]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nn1
Reaction time: 18 h

Procedure:
A solution of 6-(trifluoromethyl)-3-pyridazinecarboxylic acid (Intermediate 9, 60 mg, 0.312 mmol), HATU (131 mg, 0.344 mmol) and DIPEA (0.164 ml, 0.937 mmol) in acetonitrile (3 ml) was stirred at room temperature under argon for 15 mins and then treated with {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5, 78 mg, 0.312 mmol). The reaction mixture was stirred for 18 hrs and evaporated under reduced pressure to remove the acetonitrile. The residue was dissolved in DCM and washed with water. The organic solution was dried over MgSO4 and evaporated under reduced pressure to afford the crude product which was purified by MDAP the title compound (39 mg) as a pale solid;