Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:30]=[CH:29][C:28]([C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:38][CH:37]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
1-(4-Aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (99.6 mg, 0.39 mmol) and 2-(4-benzoylphenoxy)acetic acid (100 mg, 0.39 mmol) were combined in pyridine (10 mL). The mixture was warmed until homogeneous and then allowed to cool. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (82 mg, 0.43 mole) was added. The reaction mixture was maintained at ambient temperature overnight and then concentrated under vacuum. The residue was partitioned between chloroform and saturated potassium carbonate solution. The layers were separated. The aqueous layer was extracted with chloroform. The organic layers were combined, dried over magnesium sulfate and then concentrated under vacuum to provide a gold oil. The oil was purified by column chromatography (silica gel eluting with 10% methanol in dichloromethane) to provide about 70 mg of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-benzoylphenoxy)acetamide as a white solid, m.p. 73-98° C. 1H NMR (500 MHz, DMSO-d6) δ 8.22 (t, J=6.0 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.42 (dt, J=8.0, 1.0 Hz, 1H), 7.25 (t, J=8.0, 1.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.58 (broad s, 2H), 4.61 (t, J=7.0 Hz, 2H), 4.56 (s, 2H), 3.18 (q, J=6.0 Hz, 2H), 1.86 (quintet, J=7.0 Hz, 2H), 1.50 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 493.2106 (493.2114 calcd for C29H27N5O3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:50][C:51]([NH2:53])=[O:52]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:20][CH2:21][N:22]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:23][CH2:24]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(CC(N)=O)CC1)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL), is added 2-bromo-acetamide (10 mg, 0.066 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 2-[4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidin-1-yl]-acetamide (136) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.41 (d, 1H), 8.27 (s, 1H), 8.21 (br, 1H), 7.93 (dd, 1H), 7.73 (m, 1H), 7.40 (dd, 1H), 7.30 (s, 1H), 4.52 (s, 2H), 4.45-4.37 (m, 1H), 4.19-4.15 (br, 2H), 3.87-3.78 (br, 2H), 2.37-2.19 (m, 2H), 2.20-2.15 (m, 1H), 1.40 (d, 6H), 1.25 (d, 6H); ESMS m/z 656.2 (M+H+).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:20](N)([NH2:23])(=[O:22])=[O:21]>C1COCC1>[CH2:1]([NH:19][S:20]([NH2:23])(=[O:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNS(N)(=O)=O
Yield: 17.2 %

Procedure:
0.270 g, (1.0 mmol) of N-octadecylamine and 0.100 g (1.0 mmol) of sulfamide in 50 ml of THF (50 mL) are stirred and refluxed for 51 h. The solvent is evaporated and the crude is purified in a chromatography column, using CH2Cl2:MeOH/NH3 9:1 as eluyent. 0.06 g of white solid are obtained. Yield 18%; mp=105-107° C.;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[Cl:30][CH2:31][C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22])=[O:33]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCN
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCNC(=O)CCl
Reaction time: 0.5 h
Yield: 53 %

Procedure:
1.68 Grams of 1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone was suspended in 100 ml of chloroform, then 5 ml of triethylamine was added thereto and stirred for 30 minutes. Under ice-cooling condition, 2 ml of chloroacetyl chloride was added little by little and stirred for 5 hours. The reaction mixture was washed with water, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate, then concentrated under reduced pressure, there was obtained 1 g (53%) of 1-(3-chloroacetylaminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone. White powdery crystals (recrystallized from ethyl acetate-n-hexane). Melting point: 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(COc2cncc(Cl)c2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1ccc(COc2cncc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a suspension of 4-{[(5-chloropyridin-3-yl)oxy]methyl}benzoic acid (Preparation 17, 0.16 g, 0.60 mmol) in THF (6 mL) was added WSCDI (0.1 g, 0.62 mmol) and the reaction was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature and methanesulphonamide (0.060 g, 0.64 mmol) and DBU (0.09 g, 0.060 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and then partitioned between DCM (30 mL) and aqueous hydrochloric acid (1 M, 8 mL). The organic layer was separated and dried over magnesium sulfate and evaporated in vacuo. The resulting crude was triturated with diethyl ether (4 mL) and methanol (1 mL) to afford the title compound as a beige solid (0.053 g, 51%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH:15]=2)[C:10]([C:26]([C:29]#[N:30])(C)C)=[CH:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:19]([N:17]([CH3:18])[C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:26][C:29]#[N:30])=[CH:9][NH:8]2)=[CH:12][CH:13]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)c1ccc2c(C(C)(C)C#N)cn(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1ccc2c(CC#N)c[nH]c2c1
Yield: 88.2 %

Procedure:
A solution of 6-(benzyl-methyl-amino)-3-(cyano-dimethyl-methyl)-indole-1-carboxylic acid tert-butyl ester (26.4 g, 90%, 58.9 mmol) in DCM-TFA (2:1,180 mL) was stirred for 20 h at 20° C. Evaporation of solvent gave a crude, which was redissolved in DCM and the solution was washed with water, aqueous sodium bicarbonate and water and dried over MgSO4. Evaporation of solvent gave a solid, which was triturated with hexane to give [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile as a solid (14.3 g). MS (ES): 304 (MH+). [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile was then treated in a manner similar to that described in Step 34D-H, but using greater than three equivalents of iodomethane, to give 6-(benzyl(methyl)amino)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][N:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[O:22][N:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)c1noc(CSc2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1noc(CS(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 5.5 g of m-chloroperoxybenzoic acid (85%) in 125 ml of CH2Cl2 was added dropwise at -70° C. under N2 to a solution of 7.5 g of 3-benzoyl-5-phenylthiomethyl-1,2,4-oxadiazole in 150 ml of CH2Cl2. The temperature of the reaction was maintained below -65° by controlling the rate of addition. After stirring further for 30 minutes, the reaction mixture was added directly to a separatory funnel containing 250 ml of 10% Na2S2O3 and 500 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 3.7 g (44%) of needles, m.p. 79°-81°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=45)[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:31][CH3:34])[CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=45)[S:18]3(=[O:29])=[O:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CN1CCN(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.41 g) in dimethylformamide (50 cc) is poured over 30 minutes into a mixture of sodium hydride (0.53 g) in a 50% dispersion in vaseline oil, and dimethylformamide (10 cc), under a current of argon, maintaining the temperature between 20 and 30° C. The reaction medium is stirred for 1 hour at a temperature of about 20° C. and then methyl iodide (0.7 cc) is added over 10 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The mixture is redissolved in distilled water (200 cc) and the organic phase is extracted with dichloromethane (4×100 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (10 cc). 2-(3-[4-(4-Fluoro phenyl)-1-p-iperazinyl]-2-methoxypropyl}naphtho[1,8cd]isothiazole 1,1-dioxide (2.1 g) is obtained, m.p. 128° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:25])[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[O:26]1CCCC1.O.[OH-].[Li+].OO>O>[C:19]1([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:25])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CC[C@H](C(=O)O)c1ccccc1
Reaction time: 3 h

Procedure:
Combine (S)-4-benzyl-3-(2-phenylpent-4-enoyl)-2-oxazolidinone (3.35 g, 10 mol), tetrahydrofuran (80 mL), and water (20 mL). Cool in an ice bath. Add lithium hydroxide hydrate (0.84 g, 20 mmol) and an aqueous solution of hydrogen peroxide (4 mL, 30%, 46.4 mmol). After 3 hours, concentrate the reaction mixture to about half volume, dilute the concentrated reaction mixture with an aqueous 1 M sodium hydroxide solution and extract twice with diethyl ether. Cool the aqueous layer in an ice bath, acidify with an aqueous 3 M hydrochloric acid solution, and extract twice with dichloromethane. Extract the combined organic layers with a saturated aqueous sodium thiosulfate solution, dry over MgSO4, filter, and evaporate in vacuo to give (S)-2-phenylpent-4-enoic acid: Rf =0.48 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[CH3:39][C:40]1[N:41]=[CH:42][O:43][C:44]=1[C:45](Cl)=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:44]1[O:43][CH:42]=[N:41][C:40]=1[CH3:39])=[O:46])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: Cc1ncoc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncoc1C(=O)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 4-methyl-1,3-oxazole-5-carbonyl chloride as the starting materials in 55% yield. LCMS for C23H20ClN6O2(M+H)+: m/z=447.2. 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.69 (s, 1H), 9.63 (s, 1H), 8.48 (d, 1H), 8.15 (s, 1H), 7.82 (m, 1H), 7.55 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.07 (dd, 1H), 6.84 (m, 2H), 2.84 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.S(Cl)([Cl:16])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
reacting the 2-(2,4,6-trichlorophenoxy)-ethanol with thionyl chloride in the presence of benzyl-trimethyl-ammonium chloride in a ratio of 1:60 by weight, at a temperature of from 50° C. to 80° C., in the presence of carbon tetrachloride as solvent to form 2-(2,4,6-trichlorophenoxy)-ethyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3Br)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)CCC>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>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:18])[C:19]3[S:20][CH:21]=[CH:22][C:23]=3[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2sccc2Br)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ncccc1CN1CCC(CC(=O)c2sccc2-c2nccs2)CC1
Yield: 99 %

Procedure:
300 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-bromo-2-thienyl)-2-oxoethyl]piperidine obtained in Example 73, 438 mg of 2-(tributylstannyl)thiazole and 42 mg of tetrakis(triphenylphosphine)palladium were suspended in 4 ml of toluene, and the mixture was heated under reflux for 2 hours under nitrogen flow. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to give 300 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[CH3:43][C:44]1[CH:45]=[C:46]([CH:58]=[CH:59][CH:60]=1)[CH2:47][C:48]1([C:54]([O:56][CH3:57])=[O:55])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCl>[C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:51]3[CH2:52][CH2:53][C:48]([CH2:47][C:46]4[CH:58]=[CH:59][CH:60]=[C:44]([CH3:43])[CH:45]=4)([C:54]([O:56][CH3:57])=[O:55])[CH2:49][CH2:50]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CCO)cc1
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(CCc2cncn2Cc2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cold (-78° C.) solution of 3-(4-cyanobenzyl)-3H-imidazol-4-ylethyl alcohol (184 mg, 0.81 mmol) and diisopropylethylamine (155 μL, 0.89 mmol) in dichloromethane (3.8 mL), trifluoromethanesulfonic anhydride (143 μL, 0.85 mmol) was added. The resulting mixture was stirred at -78° C. for 20 min., and was treated with a solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (276 mg, 0.97 mmol; Example 61, Step B) and diisopropylethylamine (186 μL, 1.07 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at -78° C. for one h., and at room temp. for two h. The resultant solution was concentrated under vacuum, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]([CH3:25])[CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCC1CCCN(C)C1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CC3CCCN(C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N-methyl-1-(1-methylpiperidin-3-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.27 (m, 1H) 1.45-1.92 (m, 3H) 2.15 (br. s., 2H) 2.37-2.47 (m, 4H) 2.57-2.75 (m, 3H) 2.96 (s, 4H) 3.28 (dd, J=12.88, 5.81 Hz, 3H) 3.49 (d, J=15.41 Hz, 1H) 7.47 (d, J=8.53 Hz, 1H) 7.52 (s, 1H) 7.84 (s, 1H) 7.89 (br. s., 1H) 8.20 (d, J=8.34 Hz, 1H) 8.49 (br. s., 1H) 8.52 (d, J=8.84 Hz, 1H); ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11](=[O:19])[C:10]=2F)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:21][C:22]([F:34])([F:33])[C:23]([C:27]1[S:31][C:30]([SH:32])=[N:29][CH:28]=1)([OH:26])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:32][C:30]4[S:31][C:27]([C:23]([OH:26])([C:22]([F:21])([F:33])[F:34])[CH2:24][CH3:25])=[CH:28][N:29]=4)=[CH:16][CH:17]=3)[O:12][C:11](=[O:19])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=c1oc2ccccc2c(-c2cc(F)cc(F)c2)c1F
Reactant: CCC(O)(c1cnc(S)s1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(O)(c1cnc(Sc2ccc3c(-c4cc(F)cc(F)c4)cc(=O)oc3c2)s1)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 4-(3,5-difluorophenyl)-fluoro-2H-chromen-2-one (0.258 g, 0.93 mmol), 1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol, (0.250 g, 1.03 mmol) and potassium carbonate (0.387 g, 2.8 mmol) in NMP was heated at 120° C. overnight. The mixture was cooled to room temperature and partitioned between aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 95:5) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 7.37 (dd, 1H), 7.00-7.04 (m, 3H), 6.41 (s, 1H), 2.66 (br s, 1H), 2.12 (q, 2H), 0.98 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=C=S.C1CCC(N=C=NC2CCCCC2)CC1.[OH-].[Na+]>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:11]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:13])=[CH:5][C:6]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1ccc(C(=O)OC)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to example 113a from 3-amino-4-methylamino-benzoic acid methyl ester, 1,3-dichloro-2-isothiocyanato-benzene with DCC and NaOH in DMF.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([O:18][CH2:19][C:20]#[CH:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([O:18][CH2:19][C:20]#[CH:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCOc1cc(C(=O)OCC)n(-c2ncccc2Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCOc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 50 mL flask containing ethyl 1-(3-chloro-2-pyridinyl)-3-(2-propynyloxy)-1H-pyrazole-5-carboxylate (i.e. the product of Step A) (0.45 g, 1.5 mmol) and 10 mL of methanol was added dropwise a mixture of 50% sodium hydroxide (0.7 g, 8.75 mmol) in water (4.0 mL). The mixture was heated to near reflux and then cooled to ambient temperature with stirring continued for 15 minutes. To this mixture was added a solution of 1 N HCl (9.0 mL) and the reaction mixture was concentrated on rotary evaporator to approximately 5 mL to precipitate a solid. The product was isolated via filtration, washed with water, and then air-dried on the filter to afford 0.31 g of the title compound as a white solid.