Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH2:17][C:18]#[N:19])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][C:8]1[CH:9]=[C:10]([CH2:17][C:18]#[N:19])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: N#CCc1cc(OC2CCCCO2)cc2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: N#CCc1cc(O)cc2ccoc12
Yield: 96.2 %

Procedure:
Dissolve [5-(tetrahydropyran-2-yloxy)benzofur-7-yl]acetonitrile (3.89 g, 0.015 mol) in methanol (100 mL) and add para-toluene sulfonic acid monohydrate (0.288 g, 0.1 equivalent). After 20 minutes extract with ethyl acetate against water, then wash with brine. Concentration in vacuo affords 2.5 g (95.5%) of the title compound as an off-white solid. HRMS(m/z): Calcd 173.0465 Found 173.0477.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:39])[C:19]#[C:20][CH2:21][N:22]2[CH2:38][CH2:37][C:25]3([N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][NH:27][C:26]3=[O:36])[CH2:24][CH2:23]2)=[CH:14][CH:13]=1.[H][H]>[Pd].C(O)C.C(Cl)(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:39])[CH:19]=[CH:20][CH2:21][N:22]2[CH2:38][CH2:37][C:25]3([N:29]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][NH:27][C:26]3=[O:36])[CH2:24][CH2:23]2)=[CH:14][CH:13]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(CC#CC(O)c1ccc(F)cc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: O=C1NCN(c2ccccc2)C12CCN(CC=CC(O)c1ccc(F)cc1)CC2
Reaction time: 0.25 h

Procedure:
To a deactivated palladium catalyst, which was prepared from 5% palladium on barium sulfate (30 mg) and quinoline (15 mg) in ethanol (6 ml) and chloroform (2 ml) by stirring for 15 minutes under hydrogen, was added a solution of 8-[4(p-fluorophenyl)-4-hydroxy-2-butynyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (0.80 g) in ethanol (3 ml), and the resulting mixture was stirred under hydrogen at 25° C until an equimolar amount of hydrogen (48 ml) was consumed. The catalyst was filtered off, and the filtrate was concentrated in vacuum and chromatographed to afford 8-[4(p-fluorophenyl)-4-hydroxy-2-butenyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one as oily materials. νC=Oneat 1700 cm-1.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)C>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:47]=[N+:48]=[N-:49])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoic acid (0.58 g, 1.67 mmol) in isopropanol (10.7 mL) was added triethylamine (0.30 mL, 2.17 mmol) and diphenylphosphoryl azide (0.47 mL, 2.17 mmol) and the reaction was stirred at room temperature for 16 hours. The orange precipitate that had formed was filtered through a fritted glass funnel, rinsed with isopropanol, and dried in a vacuum oven to provide 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoyl azide as an orange solid (188 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=2.6 Hz, 1H), 8.17-8.11 (m, 2H), 8.09-8.04 (m, 4H), 7.57 (d, J=8.4 Hz, 2H), 7.24 (d, J=2.6 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 374 ([M+H]+).
Reaction SMILES: [C:1]([C:9]1C=CC=C[CH:10]=1)(=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>O1CCCC1>[CH3:10][CH2:9][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCCCCC(=O)CC
Temperature: 25 °C

Procedure:
Anionic polymerization was also done. This was carried out in tetrahydrofuran at 0° C. by using benzophenone monothithium complex as an initiator. After a specified time, a sufficient amount of acetic anhydride was added to the solution and the resulting mixture was stirred at room temperature for several hours. The separation and purification of the polymer were similar to those described for the cationic polymerization. IR (film) 1738 (νC=O), 1125 (νC-O-C) cm-1 ; 1H NMR (CDCl3) δ6.12 (H-2eq), 5.95 (H-2ax), 3.8 4.2 (2H-6), 2.5-2.8 (H-5), 1.6 2.2 (2H-3, 2H-4); Anal. Calcd. for (C6H8O3)n ; C 56, H 6.29. Found; C 56.28 H 6.11.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH2:24]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:29]1[CH:30]=[CH:31][C:32]([N:33]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CCCCOc1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)C)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 423.23 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and 4-butoxy-aniline.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][CH2:16][C:17]1[N:18]([C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[C:26]([CH3:33])=[CH:25][CH:24]=2)[C:19]([SH:22])=[N:20][N:21]=1>ClCCl>[F:15][CH2:16][C:17]1[N:18]([C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[C:26]([CH3:33])=[CH:25][CH:24]=2)[C:19]([S:22][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:20][N:21]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2c1CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1nnc(CF)n1-c1ccc(C)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Triethylamine (0.087 mL, 0.623 mmol) and ethyl 2-bromoacetate (63 μL, 0.571 mmol) were added to a solution of 5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.144 g, 0.519 mmol) in dichloromethane (2.1 mL) and stirred at room temperature for 2 hours. The crude reaction mixture was purified by SGC (0-100% EtOAc/Hexanes) to afford ethyl 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as an off-white solid (0.168 g, 89%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=1)=[O:5].C(N(CC)C(C)C)(C)C.F[C:28]1[N:33]=[C:32]([F:34])[CH:31]=[CH:30][N:29]=1>ClCCl>[F:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([N:2]([CH3:1])[CH2:3][C:4]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=2)=[O:5])[N:33]=1
Reactant: Fc1ccnc(F)n1
Reactant: CCOC(=O)Cc1csc(NC(=O)CNC)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(F)n2)n1

Procedure:
The product of step (i) (3.0 g) was slurried in dichloromethane (100 ml) and treated with N,N-diisopropylethylamine (4.0 ml) forming a complete solution. 2,4-Difluoropyrimidine (J. Heterocyclic Chem. 1985, 22, 149) (0.6 g) was then added quickly with stirring. After 10 minutes the solvents were evaporated under reduced pressure and the residue purified by chromatography eluting with 20% ethyl acetate in isohexane. The first and minor component of the mixture to be eluted was the subtitle compound (0.77 g).
Reaction SMILES: C(#N)C([CH2:4][C:5]#[N:6])O.[H-].[Na+].[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:30]=[C:23]3[C:24]([O:26][C:27](=O)[NH:28][C:22]3=[CH:21][CH:20]=2)=O)[CH2:15][CH2:14]1)(=[O:12])[CH3:11].C[N:32](C)C=O>O>[NH2:32][C:27]1[C:4]([C:5]#[N:6])=[C:24]([OH:26])[C:23]2[C:22](=[CH:21][CH:20]=[C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:10](=[O:12])[CH3:11])[CH2:18][CH2:17]3)[CH:30]=2)[N:28]=1
Reactant: CC(=O)N1CCN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC1
Reactant: N#CCC(O)C#N
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4 g malonitrile is dissolved in 50 ml dimethylformamide and in several portions 2.4 g sodium hydride 60% dispersion is added to it. To the clear solution 8 g 5-(4-acetylpiperazin-1-yl)isatoic anhydride is added and the mixture is stirred at room temperature for 10 hours. The reaction mixture is diluted with 70 ml water and extracted with 2×30 ml ethyl acetate. The aqueous phase is evaporated to dryness at reduced pressure, the solid residue is dissolved in 20 ml water and the pH is adjusted to 6 with acetic acid. The precipitated material is filtered off and washed with water. After drying 6.5 g of the title compound is obtained (MH+: 312).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[N:8]=[CH:7][C:6]=2[S:5][CH2:4]1.[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH:26]([NH2:28])[CH2:25][N:24]1C(OC(C)(C)C)=O)=[O:22].[O:36]=[C:37]1[NH:42][C:41]2[CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=[CH:46][C:40]=2[S:39][CH2:38]1>>[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH:26]([NH:28][C:47]([C:44]2[CH:45]=[CH:46][C:40]3[S:39][CH2:38][C:37](=[O:36])[NH:42][C:41]=3[CH:43]=2)=[O:48])[CH2:25][N:24]1[CH2:2][CH:3]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[N:8]=[CH:7][C:6]=2[S:5][CH2:4]1)=[O:22]
Reactant: COc1ccc2ncc3c(c2c1)CC(CBr)CS3
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COC(=O)C1CC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CN1CC1CSc2cnc3ccc(OC)cc3c2C1

Procedure:
The titled compound is prepared as an orange viscous oil following Scheme 1 and in analogy to Example 1 using 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene, 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC)c1
Reaction time: 48 h
Yield: 52.3 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes ethanesulfonylchloride (0.131 ml, 177 mg, 1.38 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (140 mg, 52%).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25].[O:28]1CC[CH2:30][CH2:29]1>CN1CCCN(C)C1=O.[Au]>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:11][CH:10]2[CH2:9][CH2:8][CH2:30][CH2:29][O:28]2)[C:21]([OH:23])=[O:22])=[CH:16][C:15]=1[C:24]([F:25])([F:26])[F:27]
Reactant: C1CCOC1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: [Au]
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CC1CCCCO1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of diisopropylamine (7.04 mL, 49.97 mmol) in dry tetrahydrofuran (140 mL) cooled to −78° C. under argon was treated with a 2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (5.00 g, 22.51 mmol) in dry tetrahydrofuran (25 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL). The reaction mixture turned gold in color and was allowed to stir at −78° C. for 1 h. At this time, the reaction was treated with a solution of trifluoromethanesulfonic acid tetrahydro-pyran-2-yl methyl ester (7.26 g, 29.26 mmol) in dry tetrahydrofuran (100 mL). The reaction mixture was allowed to warm to 25° C., where it was stirred for 30 min. The reaction mixture then was quenched with a saturated aqueous ammonium chloride solution (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified to pH=2 using a 1N aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/7 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.20 g, 72%) as a yellow gum: EI-HRMS m/e calcd for C15H16F4O3 (M+Na)+ 343.0931. found 343.0928.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1C)[CH3:16]>>[CH2:18]([N:17]([CH2:15][CH3:16])[C:25]1[CH:20]=[CH:21][C:22]([C:10]([C:5]2[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=2[C:7]([OH:9])=[O:8])=[O:11])=[CH:23][CH:24]=1)[CH3:19]
Reactant: CCn1c(C)cc2ccccc21
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
The keto-glutaric anhydride (I) is reacted mol-for-mol with a compound such as 1-ethyl-2-methylindole (T) in the presence of a catalyst, as previously disclosed, to yield keto-acid (II).
Reaction SMILES: CO[C:3]1([C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][S:5][S:4]1.[S:17](=[O:21])(=[O:20])([OH:19])[OH:18]>CCOCC>[S:17]([O-:21])([OH:20])(=[O:19])=[O:18].[CH2:8]([C:7]1[CH:6]=[S+:5][S:4][C:3]=1[C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(=O)(O)O
Reactant: COC1(C(C)(C)C)SSC=C1CC(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Product: O=S(=O)([O-])O
Yield: 103.3 %

Procedure:
A sample of 7.8 grams of 3-methoxy-3-t-butyl-4-neopentyl 1,2 dithiole was dissolved in 16 grams of ether. To the mixture was slowly added 3.0 grams of concentrated sulfuric acid. After the exothermic reaction was completed, the solid precipitate was filtered off and there was isolated 10.1 grams (93.8% of theory) of 4-neopentyl-3-t-butyl 1,2 dithiolium hydrogen sulfate.
Reaction SMILES: O.[NH3:2].[Cl:3][C:4]1[C:22]([F:23])=[CH:21][C:7]([C:8]([NH:10][C:11]2[N:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13](OC)=[O:14])=O)=[C:6]([F:24])[CH:5]=1>C(Cl)(Cl)Cl.CO>[Cl:3][C:4]1[C:22]([F:23])=[CH:21][C:7]([C:8]2[NH:2][C:13](=[O:14])[C:12]3[CH:17]=[CH:18][CH:19]=[N:20][C:11]=3[N:10]=2)=[C:6]([F:24])[CH:5]=1
Reactant: N
Reactant: COC(=O)c1cccnc1NC(=O)c1cc(F)c(Cl)cc1F
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c(-c2cc(F)c(Cl)cc2F)nc2ncccc12
Temperature: 25 °C

Procedure:
28% ammonia water was added to a chloroform-MeOH solution of methyl 2-[(4-chloro-2,5-difluorobenzoyl)amino]nicotinate and the resultant was stirred all night at room temperature to give 2-(4-chloro-2,5-difluorophenyl)pyrido[2,3-d]pyrimidine-4(3H)-one.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C:3]([OH:17])([CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6])[C:2]([F:1])([F:18])[F:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a chilled (−70° C.) solution of 70 mg (0.25 mmol) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 1) in 2.5 mL of anhydrous THF was added a 2.0 M solution of benzyl magnesium chloride in THF. The mixture was stirred for 30 minutes and then was quenched with 15 mL of saturated aqueous ammonium chloride and extracted with five 5 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using hexanes to load the sample, and then eluted with hexanes and then EtOAc-hexanes (0.5:99.5, then 1:99) to afford 58 mg (62%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:38])=[C:6]([CH3:37])[C:7]2[N:8]([C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH3:2].CO.Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([CH3:38])=[C:6]([CH3:37])[C:7]2[N:8]([C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([NH2:23])[CH2:20][CH2:21][CH2:22]4)=[CH:17][CH:18]=3)[N:12]=2)[N:9]=1)[CH3:2]
Reactant: CCOc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCOc1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of the tert-butyl {1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-36 (210 mg, 0.410 mmol, 1.0 eq) in DCM (2.64 mL) and MeOH (1.66 mL) was added a solution of 4 M hydrogen chloride in dioxane (2.05 mL, 8.19 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline, treated with DCM and filtered through a phase separator. The volatile components of the organic phase were removed in vacuo to give 145 mg (82% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>CN(C1C=CN=CC=1)C.ClCCl.CCOC(C)=O>[C:26]([O:1][C:2]([CH3:18])([CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])[CH3:17])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(O)CCOc1cccc([N+](=O)[O-])c1C#N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCOc1cccc([N+](=O)[O-])c1C#N
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 2-(3-hydroxy-3-methylbutoxy)-6-nitrobenzonitrile (Example 231d) (250 mg, 1 mmol), triethylamine (3 equiv.), and DMAP (0.1 equiv.) in dry dichloromethane (20 mL) was added dropwise acetyl chloride (1.5 equiv.) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C.—room temperature overnight. The reaction was diluted with EtOAc, washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound (137 mg, 47%). MS 293 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:23]([NH2:24])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2].[CH3:25][CH2:26][C:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[C:23]([NH:24][CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCC(=O)CC
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1NC(CC)CC
Reaction time: 3 h

Procedure:
To a solution of 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine (100 mg) in acetic acid (10 mL) there was added 3-pentanone (0.04 mL), and then sodium triacetoxyborohydride (85.0 mg) was slowly added at room temperature and the mixture was stirred for 3 hours. A 5 N aqueous sodium hydroxide solution was added while cooling on ice, and then extraction was performed with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (10 g), and the title compound (69 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Br)([Br:12])=O>ClCCl>[Br:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(CO)ccn1
Reactant: O=S(Br)Br
Solvent: ClCCl
Product: Cc1cc(CBr)ccn1
Reaction time: 1 h

Procedure:
To a solution of (2-methylpyridin-4-yl)-methanol (0.510 g, 4.14 mmol) in 8 mL of dichloromethane was added thionyl bromide (1.03 g, 4.97 mmol) dropwise. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride. The organic solution was washed 2× with water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 4-(bromomethyl)-2-methylpyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 188.0 (81Br) for [M+H]+.