Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](Cl)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Yield: 84 %

Procedure:
21.7 g of 2-(3,4-dimethoxyphenyl)ethylamine are dissolved in 150 cc of anhydrous chloroform and then the solution is added to 15.2 g of anhydrous triethylamine. The solution is cooled at a temperature between 5° and 10° C. and then, under stirring, there is added the 3,4-dimethoxyphenylacetyl chloride prepared in part (a), 26 g, dissolved in 80 cc of anhydrous chloroform. The temperature is allowed to rise to room temperature. It is then warmed under reflux for eight hours. After cooling the mixture, by addition of an additional portion of chloroform, 200 cc, the organic phase is washed with water and then with 5% hydrochloric acid and an additional amount of water, then 5% sodium hydroxide and finally water. The organic phase is dried over anhydrous sodium sulfate and after filtering, the solvent is evaporated under reduced pressure. The solid thus obtained is recrystallized from absolute ethanol. The pure amide, 36 g, is obtained in a yield of 84%, m.p. 128° C. The substance gives a single spot on chromatography using ethanol as eluent.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].Cl[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:14]([O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:15]([CH3:16])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1F
Yield: 65.3 %

Procedure:
5.8 g of 2,3-difluoro-6-nitrophenol, 5.0 g of monochloroacetone, 8.0 g of potassium carbonate and 0.8 g of potassium iodide were added to 100 ml of acetone and the mixture was refluxed for 4 hours. After the removal of insoluble material by filtration, the solvent was evaporated and the residue was distributed between chloroform and water. The chloroform layer was washed with water and was dried, then the solvent was evaporated. The residue was treated with n-hexane to provide 5.0 g of 2-acetonyloxy-3,4-difluoronitrobenzene as light yellow crystals with m.p. 61° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:61]([O:63]CCCC)=[CH2:62]>C(O)CO.C(Cl)Cl.Cl.[Pd](Cl)Cl>[C:61]([C:14]1[C:15]([O:22][CH3:23])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:63])[CH3:62]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: C=COCCCC
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: OCCO
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C(C)=O)c1OC
Temperature: 140 °C

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.82 g), triethylamine (0.7 ml), 1,3-bis(diphenylphosphino)propane (0.04 g) and palladium chloride (0.01 g) in ethylene glycol (4 ml) was sealed in a vial under nitrogen and the mixture was stirred and heated to 140° C. Butyl vinyl ether (0.8 ml) was then added and the resultant mixture was stirred and heated at 140° C. for 2 hours. After cooling, the mixture was diluted with DCM and 1M hydrochloric acid was added. The mixture was stirred at room temperature for 30 minutes then the two layers were separated and the aqueous layer was extracted with further DCM. The combined organic layers were dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-80%) to give crude ethyl 3-acetyl-6-(benzenesulphonylmethyl)-2-methoxybenzoate (0.33 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16]1[S:20][C:19]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COC(=O)Cc1sc(N)nc1-c1ccccc1
Product: COC(=O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Yield: 32.1 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[CH3:6][C:7]1[CH:8]=[C:9]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][C:30]3([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:28]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CCOC(C)=O.O>[OH:36][C:30]1([CH2:29][N:27]2[CH:28]=[C:24]([C:9]3[CH:10]=[C:11]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][N:15]=4)[CH:12]=[C:7]([CH3:6])[CH:8]=3)[CH:25]=[N:26]2)[CH2:35][CH2:34][N:33]([C:2]([NH2:3])=[O:1])[CH2:32][CH2:31]1
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3(O)CCNCC3)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC3(O)CCN(C(N)=O)CC3)c2)c1
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
Potassium cyanate (55.6 mg, 0.69 mmol), water (2.4 mL) and hydrochloric acid (2.0 M in water, 0.3 mL, 0.60 mmol) were added to a solution of racemic 4-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)piperidin-4-ol (49 mg, 0.11 mmol) in THF (0.8 mL). The mixture was stirred at 55° C. for 3.5 hours. Additional hydrochloric acid standard solution (2.0 M in water, 0.15 mL, 0.30 mmol) and potassium cyanate (20.0 mg, 0.25 mmol) were added. The mixture was heated for another 2 hours then saturated sodium bicarbonate and EtOAc were added. The organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford 4-hydroxy-4-((4-(3-methyl-5((4-(trifluoromethyl) pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl) piperidine-1-carboxamide. MS ESI calc'd for C22H25F3N7O2 [M+H]+476. found 476. 1H NMR (500 MHz, CD3OD) δ 8.68 (d, J=4.9, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 7.09 (d, J=4.9, 1H), 4.16 (s, 2H), 3.78 (d, J=13.2, 2H), 3.20 (t, J=11.3, 2H), 2.35 (s, 3H), 1.71-1.56 (m, 2H), 1.48 (d, J=13.1, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si](OCC)(OCC)OCC.[C:15]1(C=[CH:21][C:19](O)=[CH:18][CH:17]=1)[OH:16]>C1(C)C=CC=CC=1>[O:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:21][C:4]=2[CH:3]=[CH:2][NH:1]1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 65 %

Procedure:
This compound was prepared according to the method described previously using 3-aminopropyltriethoxysilane (22.1 g, 100 mmole), paraformaldehade (6.3 g, 210 mmole), hydroquinone (5.5 g, 50 mmole), and toluene (150 ml). The final product was a viscous liquid. The yield was 65% of theory.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:3]([C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(C)c1C(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1C(=O)C(C)(C)C

Procedure:
A mixture of methyl 3-methyl-2-(2,2-dimethylpropanoyl)benzoate, N-bromosuccinimide and benzoylperoxide in of anhydrous carbon tetrachloride is stirred at reflux for about 1.5 hours. After cooling to room temperature the formed succinimide is collected by suction and washed with cold carbon tetrachloride. The mother liquors are evaporated to dryness in vacuo and the residue is rinsed with diethyl ether and collected by suction filtration to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH2:9][S:10]([C:13]3[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=3)(=[O:12])=[O:11])=[C:7]([CH3:20])[O:6][N:5]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:27][CH:9]([S:10]([C:13]1[CH2:17][C:16]([CH3:18])([CH3:19])[O:15][N:14]=1)(=[O:11])=[O:12])[C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][O:6][C:7]=1[CH3:20]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1onc(C2CC2)c1CS(=O)(=O)C1=NOC(C)(C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C2CC2)c1C(Cl)S(=O)(=O)C1=NOC(C)(C)C1
Temperature: -78 °C
Yield: 44.2 %

Procedure:
3-Cyclopropyl-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfonylmethyl)-5-methyl-isoxazole (108 mg, 0.36 mmol) was dissolved in THF (5 ml) under nitrogen. The solution was cooled to −78° C. and potassium tert-butoxide (0.4 ml, 0.4 mmol) added, followed by hexachloroethane (90 mg, 0.4 mmol). The solution was allowed to warm to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 3.07 of Table 29) as a white solid (53 mg, 44% yield).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cccc(Cl)c1
Agent: N
Product: Clc1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ7.49 (s, 1H), 7.51-7.59 (m, 2 H), 7.85-7.91 (m, 1H), 7.94-8.04 (m, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.5, 1.5 Hz, 1H), 9.30 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 258 (M+H)+, 260 (M+H)+.
Reaction SMILES: [C:1]12([CH:11]([NH:15][CH3:16])[C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:50]/[C:51](=[CH:57]\[C@@H:58]([N:62]([CH3:71])[C:63](=[O:70])[C@H:64]([C:66]([CH3:69])([CH3:68])[CH3:67])[NH2:65])[CH:59]([CH3:61])[CH3:60])/[C:52]([O:54][CH2:55][CH3:56])=[O:53].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]12([C@@H:11]([NH:15][CH3:16])[C:12]([NH:65][C@H:64]([C:63]([N:62]([CH3:71])[C@@H:58]([CH:59]([CH3:61])[CH3:60])/[CH:57]=[C:51](\[CH3:50])/[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CNC(C(=O)O)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](NC)C12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To adamantan-1-yl-methylamino-acetic acid (0.447 g, 2.0 mmol, from Reference Example 6) in dichloromethane (17 mL) is added PyBOP (1.04 g, 2.0 mmol). After 15 min ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.625 g, 2.0 mmol, WO 99/32509) in dichlormethane (5 mL) is added, followed by diisopropylethylamine (0.75 mL, 4.3 mmol). This is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo and the residue treated with ethyl acetate and water. The ethyl acetate layer is dried over sodium sulfate and purified by hplc. The two diastereomers are partially separated. The first isomer is assigned the SSS configuration and contained 33.4% of the RSS isomer. MS: m/z 518.3 (M+1). The second isomer is assigned the RSS configuration and contained 8.9% of the SSS isomer. MS: m/z 518.3 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.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>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Temperature: 90 °C
Yield: 78.5 %

Procedure:
To a mixture of 3-(1-BOC-2-(R)-azetidinylmethoxy)-5-bromo-6-chloropyridine (0.25 g, 0.68 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 1%), aqueous sodium carbonate (2.0 M, 1 mL) in toluene (10 mL), was added phenylboronic acid (0.108 g, 0.89 mmol). The reaction mixture was stirred and heated at 90° C. for 16 h. Solvent was evaporated. The residue was chromatographed (silica gel; hexane/EtOAC, 10:1 to 2:1) to afford an oil (0.20 g, 78%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 4H), 1.58 (s, 5H), 2.24-2.40 (m, 2H), 3.89 (t, 2H, J=7.5 Hz), 4.15 (dd, 1H, J=3.0, 10.0 Hz), 4.36 (m, 1H), 4.52 (m, 1H), 7.27 (d, 1H, J=3.0 Hz), 7.45 (s, 5H), 8.12 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 347 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:20])[C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.CN(CCN(C)C)C.[CH:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[C:30]1=[O:39])[CH2:36]2>CCCCCC.C1COCC1.O>[CH3:20][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([CH:11]([C:30]2([OH:39])[CH:31]3[CH2:37][CH:35]4[CH2:34][CH:33]([CH2:38][CH:29]2[CH2:36]4)[CH2:32]3)[C:12]2[NH:16][CH:15]=[CH:14][N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)c1cccc(Cc2ncc[nH]2)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CN(C)c1cccc(C(c2ncc[nH]2)C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
20 ml (31 mmol) of a 1.55 molar solution of n-butyllithium in hexane were added dropwise to a solution of 3.03 g (15 mmol) of (3-dimethylaminobenzyl)-imidazole and 1.75 g (15 mmol) of TMEDA in 30 ml of absolute THF. Stirring was carried out for 1 hour at -70° C., after which a solution of 2.26 g of adamantanone in 40 ml of absolute THF was added dropwise at -30° to -15° C. The mixture was allowed to warm up to room temperature in the course of about 45 minutes and was stirred for a further 2 hours at room temperature, 400 ml of water were added at 10° C., while cooling, and stirring was continued for 15 minutes at 0°-5° C., a crystalline precipitate being formed. This was filtered off under suction, rinsed with hexane and diisopropyl ether and dried in vacuo. 2.20 g (= 41.7% yield) of pure (3-dimethylaminophenyl)-(2-hydroxy-2-adamantyl)-1-imidazolylmethane of melting point 185° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[H][H]>CN(C=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCCC=Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: OCCCCc1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To the alcohol (3 g) (Step I) in DMF (50 mL) was added 10% Pd/C (300 mg). Hydrogen was added (balloon) and the mixture was vigorously stirred for 4 hours. The reaction mixture was filtered, H2O was added, the mixture was extracted with ethyl acetate and the organic extracts dried and evaporated. Flash chromatography of the residue using 40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:26]=[N:25]1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1

Procedure:
The subtitled compound (834 mg) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a similar method to that described in Example 18, Step i). MS M+H-C4H8]+=319 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.72 (s, 1H), 7.37-7.22 (m, 3H), 7.07 (d, J=7.5 Hz, 1H), 4.32 (t, J=5.2 Hz, 2H), 3.78 (t, J=5.3 Hz, 2H), 3.70 (t, J=6.5 Hz, 2H), 3.68 (t, J=7.5 Hz, 2H), 3.35 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.47 (s, 9H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1.C(OCC)(=O)C.ClCCl>C(C(C)=O)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:13])[CH2:19]2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C[C@@H]1CNCCN1
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,4-dichlorophthalazine (5.00 g, 25.1 mmol) and (R)-2-methylpiperazine (6.29 g, 62.8 mmol) were dissolved in methyl ethyl ketone (80 mL) and stirred at rt for 2 days. The reaction was added to ethyl acetate (350 mL) and washed once with aqueous K2CO3 (10%), once with water, and once with saturated sodium chloride. The organic phase was dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of dichloromethane/0-5% methanol gave a pale yellow solid. MS (M+H)+=263.1.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.[ClH:24]>C(Cl)Cl>[ClH:24].[ClH:24].[CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Yield: 99 %

Procedure:
(R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was treated with HCl (4M in dioxane, 6 mL) in DCM (20 mL) for 6 hours to provide (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.55 g, 99%). MS (APCI+) [M+H]+219.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:9]1[CH:14]=[CH:13][C:37]([C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:11][CH:10]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2c(C(=O)OCC)cnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-ethylcarboxylphenylboronic acid (107 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(4-ethoxycarbonyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].[Cl-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)c1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 166.1 %

Procedure:
Tetrahydrofuran (100 ml) was added to sodium hydride (1.94 g, 45 mmol) under an atmosphere of nitrogen. To the suspension was added a tetrahydrofuran solution of 1-(3-hydroxyphenyl) ethanone (5.05 g, 37 mmol) in an ice bath. After stirring the mixture for 15 minutes dimethylcarbamyl chloride (1.7 ml, 19 mmol) was added dropwise into the mixture and the resulting mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium chloride solution was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford the desired compound (6.54 g).