Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.I[CH2:23][CH2:24][CH3:25].[Na]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:23][CH2:24][CH3:25])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Agent: [Na]
Solvent: C1CCOC1
Product: CCCN(c1cncc(Cl)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate (0.20 g, 0.64 mmol) in tetrahydrofuran (3 mL) at 0° C. was added 1-iodopropane (1 mL, 10 mmol) and sodium hyrdride (0.051 g, 1.3 mmol). The reaction mixture was warmed to room temperature then stirred at 60° C. After 1.5 h, the reaction mixture was cooled to room temperature and quenched with water (10 mL). The reaction mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)(propyl)amino]piperidine-1-carboxylate as a yellow oil. LRMS (ESI) calculated for C17H27ClN4O2 [M+Na]+, 377.2; found 377.1.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16]([CH3:18])=O>>[CH:16]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Product: CC(C)N1CC2CC1CN2C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and using acetone as described in EXAMPLE AAA1, Step A.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>O>[C:14]1(=[O:16])[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCCc1cccc2ccccc12
Solvent: O
Product: O=C1CCCc2c1ccc1ccccc21
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To 4-(1-naphthyl)butanoic acid (3.52 g) was added polyphosphoric acid (35.0 g) and the mixture was stirred at 40° C. for 20 h. The reaction was then diluted with water (200 cm3) and extracted with dichloromethane (3×100 cm3). The organic extracts were washed with water, aqueous sodium hydrogen carbonate solution (0.5 M) and then saturated aqueous sodium chloride solution. It was then dried (Na2SO4) and the solvent was removed under reduced pressure to afford the title compound as an oil that solidified on standing (3.09 g).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(OS(C(F)(F)F)(=O)=O)C=C2)(=O)C(C)(C)C.C([O:47][CH2:48][C@H:49]([C:55]1[C:56]([C:73]2[CH:78]=[CH:77][C:76]([Cl:79])=[CH:75][CH:74]=2)=[C:57]2[C:62](=[CH:63][C:64]=1[CH3:65])[N:61]=[C:60]([C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[CH:59]=[CH:58]2)[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])(=O)C(C)(C)C>>[Cl:72][C:69]1[CH:68]=[CH:67][C:66]([C:60]2[CH:59]=[CH:58][C:57]3[C:62](=[CH:63][C:64]([CH3:65])=[C:55]([C@H:49]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:48][OH:47])[C:56]=3[C:73]3[CH:78]=[CH:77][C:76]([Cl:79])=[CH:75][CH:74]=3)[N:61]=2)=[CH:71][CH:70]=1
Reactant: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
(S)-2-(2,5-Bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethanol (compound of Example 26), except that (S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): 480.2, 482.2, 484.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2.[OH:24]O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3ccccn3)ccc2N1
Solvent: CC(=O)O
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccn3)ccc2N1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
32.8 gm (0.1 mol) of 6-[4-(2-pyridyl-mercapto)-butoxy]-3,4-dihydro-carbostyril were dissolved in 330 ml of glacial acetic acid, and 10.2 gm (0.105 mol) of 35% hydrogen peroxide were added. The solution was stirred for 15 hours at about 20° C. The glacial acetic acid was distilled off at 60° C. in vacuo, the residue was washed with ether, and the thus obtained crude product was recrystallized twice from xylene in the presence of activated charcoal. Colorless crystals with a melting point of 144.5°-146° C. were obtained. Yield: 27.5 gm (79.8% of theory).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#N)[C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1.[OH2:22]>C(O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:22])=[O:1])[C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CCc1c(C#N)cccc1S2
Reactant: O
Agent: [K+]
Solvent: CCO
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2
Yield: 69 %

Procedure:
An amount of 6.0 g potassium hydroxide was dissolved in 20 ml of 80% ethanol and to the solution was added 1 g of 2-methoxy-9-cyano-10,11-dihydrodibenzo[b,f]thiepin and the resulting mixture was refluxed for 26 hours. The mixture was freed of the solvent under reduced pressure to obtain the residue, which was dissolved in water and extracted with ethyl acetate. The aqueous layer was acidified with conc. hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and freed of the solvent to give 743 mg (69%) of 2-methoxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin as pale reddish needles having a melting point of 185°-186° l C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH4+:11].[OH-]>COCCOC>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:11])=[O:8]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [OH-]
Solvent: COCCOC
Product: NC(=O)c1cncc(Br)c1
Reaction time: 1.5 h

Procedure:
All of the 5-bromonicotinoyl chloride prepared above was dissolved in 100 ml hot 1,2-dimethyoxyethane and added slowly during about 15 min to 500 ml cold, concentrated NH4OH in a 1 l round-bottom flask. The mixture was then stirred 1.5 hr at -10° C. to about 5° C. followed by filtration to collect white crystalline plates of 5-bromonicotinamide which were dried at 56° C. for 1.0 min to afford 17.79 g (89.2% yield) mp 222°-223° C. (lit. 224°-225° C., Czuba, W., Rec Trav Chim (1963) 82: 988-996; lit 141°-142° C., Morisawa, Y., J Med Chem (1977) 20: 129).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12]OC(C)(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:24])[CH:21]([CH3:23])[CH3:22]>>[C:1]1([CH2:7][C:8]([O:24][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)CO
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [C]=O
Product: CC(C)COC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
Toluene (1.38 g), isobutanol (74 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 69 mg isobutyl phenylacetate was obtained by column chromatography, in a yield of 72%. 1HNMR (400 MHz, CDCl3) δ 0.88 (s, 3H), 0.89 (s, 3H), 1.85-1.96 (m, 1H), 3.62 (s, 2H), 3.86 (d, J=6.8 Hz, 1H), 7.23-7.34 (m, 5H); 13CNMR (100 MHz, CDCl3) δ 19.0, 27.7, 41.5, 70.9, 127.0, 128.5, 129.3, 134.3, 171.6; HRMS (ESI) calcd. for C12H16NaO2 [M+Na]: 215.1043. found: 215.1037. The isobutyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 53 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[N:29]=[C:28]([Cl:30])[N:27]=[C:26]2[N:31]([CH3:34])[N:32]=[CH:33][C:25]=12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:30][C:28]1[N:27]=[C:26]2[N:31]([CH3:34])[N:32]=[CH:33][C:25]2=[C:24]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[S:11])=[CH:3][C:2]=2[F:1])[N:29]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol), 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (15.3 mg, 0.075 mmol, preparation: J. Org. Chem. 1958, 23, 852, the disclosure of which is herein incorporated by reference) and K2CO3 (10 mg, 0.075 mmol) was added DMF (2 mL). The reaction was stirred at RT for 24 h. The reaction was quenched with water (2 mL) and CH2Cl2 (5 mL). The organic layer was separated, dried with sodium sulfate, concentrated in vacuo and purified by reverse phase preparative HPLC to give the title compound (22.9 mg, 60%) as a white solid. MS(ESI+) m/z 457 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])/[C:6](/[NH:18][C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:36])/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:22][C:21]=1[Cl:37])=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.Cl>O>[Cl:37][C:21]1[CH:22]=[C:23]([CH:26]([OH:36])/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18]/[C:6](=[CH:7]\[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[C:5]([OH:39])=[O:4])=[O:38]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.6 mL, 0.6 mmol) was added to a suspension of rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 230; 95 mg, 0.184 mmol) in water (2 mL). The reaction mixture was stirred at room temperature for 16 h and then acidified with 1N hydrochloric acid solution (0.6 mL). The mixture was stirred for 1 h, then the solid was filtered off, washed with water, dried and purified by reverse phase HPLC and lyophilized to give rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (57 mg, 62% yield) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.Cl>CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(C=C2CCc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 83.6 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dimethoxybenzaldehyde 1.23 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for 5.5 hours under reduced pressure to obtain the desired compound 1.60 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:15](\[C:13]#[N:14])/[C:16]([O:18][CH3:19])=[O:17])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: COC(=O)CC#N
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 84 %

Procedure:
Following the general method as outlined for Intermediate 1, starting from 6-chloro isatin and methyl cyanoacetate, the title compound was isolated, after evaporation, as a dark brown solid in 84% yield. This was a 5.5:1 mixture of geometric isomers (98% purity by HPLC).
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:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[NH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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:22]=[CH:21][C:19]([NH:20][C:30]([NH:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:36])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: NN1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Yield: 51.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (35 mg, yield 51%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:25])[CH2:5][O:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C:10]([C:22](=[O:24])[CH3:23])=[CH:9][CH:8]=1.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH:29]=O>C(O)C.O>[CH3:25][C:4](=[CH2:3])[CH2:5][O:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[C:10]([C:22](=[O:24])[CH:23]=[CH:29][C:28]2[C:27]([Cl:26])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[CH:9][CH:8]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C=C(C)COc1ccc(C(C)=O)c2oc3ccccc3c(=O)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)COc1ccc(C(=O)C=Cc2c(Cl)cccc2Cl)c2oc3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(2-methylallyloxy -4acetyl-xanthen-9-one (2.31 g, 0.0075 mol) and 2,6dichloro-benzaldehyde (1.31 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.1 g of product m.p. 135-137° C., 1H-NMR (CDCl3)δ:4.74 (m, 2H), 5.4 (m, 2H), 5.95 (m, 1H), 7.06-8.5 (m, 11 H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[H-].[Na+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=[C:4]([S:18][CH3:19])[N:5]=1
Reactant: Oc1ccccc1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1nc(Nc2ccccc2Cl)c(C=O)c(Oc2ccccc2)n1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a solution of 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (315 mg, 1 mmol) in 10 mL of anhyd DMSO was added NaH (50 mg, 1.2 mmol, 60% dispersion in mineral oil, 1.2 eq) followed by phenol (112 mg, 1.2 mmol, 1.2 eq). The reaction mixture was stirred for 1 h 23°, quenched with H2O (20 mL), Et2O (100 mL) was added and the layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4) filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 120 mg (45% yield) of 4-(2-chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.32 (s, 3H), 7.01-7.49 (m, 8H), 8.51 (d, 1H, J=7.2 Hz), 10.49 (s, 1H), 11.58 (br s, 1H). LC MS (m/e)=372 (MH+). Rt=2.94 min.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2]([Cl:4])=[O:3].O[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl.CN(C=O)C>[C:1]([Cl:6])(=[O:5])[C:2]([Cl:4])=[O:3].[Cl:4][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CO)cc3)nc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CCl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (42 μL, 0.47 mmol) was added to a solution of 1-methylethyl 4-[({6-[4-(hydroxymethyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.165 g, 0.43 mmol) in CH2Cl2 (5 mL) and DMF (0.5 mL) at 0° C. The mixture was warmed to ambient temperature and stirred for 1 h. Removal of CH2Cl2 and excess of oxalyl chloride under reduced pressure gave crude 1-methylethyl 4-[({6-[4-(chloromethyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a dark brown oil. Crude 1-methylethyl 4-[({6-[4-(chloromethyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate was mixed with sodium thiomethoxide (64 mg, 0.86 mmol) in DMF and heated at 100° C. overnight. Additional sodium thiomethoxide (64 mg, 0.86 mmol) was added, and the heating was continued at 100° C. overnight. Cooled to ambient temperature, the mixture was poured into water and extracted with Et2O. The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a yellow solid. The crude material was purified by chromatography on a silica gel column eluted with 1:11 EtOAc/CH2Cl2 to 1:8 EtOAc/CH2Cl2 to give 32 mg (18%) of 1-methylethyl 4-{[(6-{4-[(methylthio)methyl]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylateas a white solid. LRMS (ESI), m/z 415 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.837 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organics were separated and dried over sodium sulfate and concentrated. The product was used without further purification ESI-MS m/z: 211 (M+1), UV retention time: 1.25 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][SH:24])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:23][S:24][CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14]
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: SCc1ccc(Cl)c(Cl)c1
Product: O=C1CCCc2c1ccc(O)c2CSCc1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Yield: 63.5 %

Procedure:
5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) and (3,4-Dichloro-phenyl)-methanethiol (1.0 mL, 6.0 mmol) were sealed in a 16×120 mm screw capped tube and heated to 40° C. overnight. The excess (3,4-Dichloro-phenyl)-methanethiol was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate/acetic acid, 58:40:2) to give 350 mg (63%) of the desired product as a tan powder: (LC-MS, APCI) m/z 367/369 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>Br.O>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[CH:11]=[N:10][N:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[CH:13]=2)[CH:15]=1
Reactant: COc1cccc(-n2cc(-c3cccnc3)cn2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(-n2cc(-c3cccnc3)cn2)c1
Temperature: 25 °C
Yield: 109.6 %

Procedure:
A solution of 3-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)pyridine 4 (1.20 g, 4.77 mmol) in hydrogen bromide acid (15 mL, 48%) refluxed (110-120° C.) for 24 hours under an atmosphere of nitrogen. Then the mixture was cooled down to ambient temperature and neutralized with a solution of K2CO3 in water until there was no gas to generate. Then the precipitate was filtered off and washed with water several times. The collected solid was dried in air to afford the product as a brown solid 1.24 g in 99% yield. 1H NMR (DMSO-d6, 400 MHz): δ 6.59 (dt, J=7.2, 2.0 Hz, 1H), 7.11-7.17 (m, 3H), 7.38 (dd, J=7.6, 1.6 Hz, 1H), 8.07 (dt, J=8.0, 2.0 Hz, 1H), 8.15 (s, 1H), 8.33-8.34 (m, 1H), 8.85 (d, J=1.6 Hz, 1H), 8.90 (s, 1H), 9.78 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:26]#[C:25][CH:27]3[CH2:29][CH2:28]3)=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: C#CC1CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(C#CC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 112, using 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and ethynylcyclopropane as starting materials to yield the product as an off-white solid, MS (ISP) 395.3, 397.2 (M+H)+.