Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][O:3]1.[C:12]([O:20]CC=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]([C@H:5]1[CH2:4][O:3][CH:2]([CH2:11][O:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6]1)=[O:8]
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Reactant: O=CCOC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1COC(COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of methyl-α,β-isopropylidene-D-glycerate (II) (Fluka: registry # 52373-72-5), (9.76 g, 60.9 mmol, 1 eq) and benzoyloxyacetaldehyde I (10 g, 60.9 mmol, 1 eq) in toluene (20 mL) at 80° C., p-toluenesulfonic acid (PTSA) (460 mg, 2.4 mmol, 4 mol %) was added. The reaction flask was kept under vacuum for one hour and a distillate was collected (80-85° C.) during this period of time. The residue was then cooled to room temperature (RT) and purified by column chromatography on silica gel, using hexanes/ethyl acetate as eluent to produce 13.2 g (81%) of the title compound as a mixture of cis and trans isomers in a ratio of 3:1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:42]([NH2:44])=[O:43])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH2:36][C:37]5S[CH:39]=[CH:40][CH:41]=5)[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].S1C=CC=C1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:42]([NH2:44])=[O:43])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41][CH2:40][CH2:39][O:4]5)[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5cccs5)c4)cc23)CC1
Agent: NCc1cccs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Yield: 74.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide trifluoroacetate, substituting 1-[(2S)-tetrahydro-2-furanyl]methanamine (31.5 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 39.2 mg of the title compound (74.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=O)[C:5]=2[CH2:4][O:3]1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=[C:6]2[C:2]([CH3:16])([CH3:1])[O:3][CH2:4][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Product: CC1(C)OCc2c1nc1ccccc1c2Cl
Temperature: 0 °C

Procedure:
A solution of the compound of formula VI, 3,4-dihydro-3,3-dimethylfuro[3,4-b]quinolin-9(1H)-one (6.5 g, described in Example 8), in phosphorus oxychloride (26 ml) is stirred vigorously at room temperature for one hour. The solution is added to 340 ml of crushed ice. The mixture is stirred and the precipitate is removed by filtration. The filtrate is diluted with ice-water (600 ml) and made alkaline with 30% sodium hydroxide solution (75 ml). The precipitate is collected and crystallized from petroleum ether to give the title compound, mp 108°-110° C. The hydrochloride salt of the title compound melts at 189°-194° C.
Reaction SMILES: C([Li])CCC.[Br-].[N:7]1([CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(OC[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)=O)C>CCCCCC.C1COCC1>[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)[CH2:13][CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOCn1ccnc1C(=O)c1ccc(C)cc1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(CCN2CCCC2)c2ncc[nH]2)cc1
Reaction time: 0.08 h
Yield: 106.4 %

Procedure:
A solution of n-butyl lithium in hexane (1.6 M, 7.7 ml) was added dropwise under nitrogen with stirring to a suspension of 2-(1-pyrrolidyl)ethyltriphenylphosphonium bromide (5.41 g) in dry THF (75 ml) keeping the temperature at -10° to -5°. The addition was complete after 5 min. The mixture was then stirred at 0° for 20 min. then cooled to -5° and treated with a solution of (1-ethoxymethylimidazol-2-yl)-4-methylphenylmethanone (3.0 g) in dry THF (30 ml). The mixture was stirred at room temperature for 16 h. and then the precipitated triphenylphosphine oxide was filtered off and washed with a little THF (10 ml). The filtrate and washings were combined and concentrated in vacuo to a yellow syrup. This was absorbed from chloroform (3 ml) onto a column of silica gel (Merck Kieselgel 60, 200 g). Removal of the solvent afforded isomers of the title compound as a thick yellow brown syrup (3.52 g) which was used in the next stage without further purification.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:97]=[CH:98][CH:99]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([NH:72][CH:73]5[CH2:78][CH2:77][N:76]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:75][CH2:74]5)[CH:69]=[CH:70][CH:71]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[C:53]([CH3:96])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:97]=[CH:98][CH:99]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[C:68]([NH:72][CH:73]5[CH2:78][CH2:77][N:76]([C:79]([O:81][C:82]([CH3:83])([CH3:84])[CH3:85])=[O:80])[CH2:75][CH2:74]5)[CH:69]=[CH:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[C:53]([CH3:96])=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(NC4CCN(C(=O)OC(C)(C)C)CC4)c3)cc12
Yield: 67.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-((3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (150 mg, 0.200 mmol) was hydrolyzed by lithium hydroxide (17 mg, 0.401 mmol) in THF/methanol/water (5/1/1 ml) to yield 80 mg (67.2% yield) of the titled compound after column purification using 2% methanol in DCM as eluent. MS: m/z=594.8 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:19][C:20]([C:22]2[N:26]3[CH:27]=[CH:28][C:29](F)=[CH:30][C:25]3=[N:24][CH:23]=2)=[O:21])[N:12]([CH2:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH3:39])[N:34]=2)[N:11]=1)[CH3:9]>C1OCCOC1.CN(C)C=O>[CH2:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:19][C:20]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[CH:30][C:25]3=[N:24][CH:23]=2)=[O:21])[N:12]([CH2:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH3:39])[N:34]=2)[N:11]=1)[CH3:9]
Reactant: c1nc[nH]n1
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(-n5cncn5)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1H-1,2,4-triazole was dissolved in 4-dioxane and treated with sodium hydride (20 mg, 0.48 mmol, 60% dispersion in mineral oil) with stirring at ambient temperature for 30 minutes. N-(3-Ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (35 mg, 0.08 mmol) was added as a solution in N,N-dimethylformamide. The mixture was heated to 98° C. and stirred for 2 days. The mixture was quenched by the addition of water. A precipitate formed and the solid was isolated by filtration, washed with water and dried under vacuum to give N-(3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (39 mg). MS m/z 481.1 (M+1, APCI+).
Reaction SMILES: Cl/[C:2](/[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[CH:3]/[CH:4]=O.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[O-]CC.[Na+]>CCO.CCOC(C)=O>[NH:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]([C:2]2[S:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=2)=[CH:7]1
Reactant: CCOC(=O)CS
Reactant: O=C/C=C(/Cl)c1c[nH]c2ncccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2c[nH]c3ncccc23)s1
Yield: 74 %

Procedure:
(E)-3-chloro-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylaldehyde (0.9 g. 4.3 mmol) was dissolved in EtOH (20 mL) and ethyl 2-mercaptoacetate (0.76 g, 6.3 mmol) and sodium ethoxide (1.0 g, 14.7 mmol) were added. The reaction mixture was heated to reflux for 90 minutes. The reaction mixture was diluted with EtOAc and the organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a solid, which was purified by column chromatography on silica (20 to 100% EtOAc/hexanes) to give the product, 890 mg, 3.3 mmol, 74% yield. 1H NMR 500 MHz (DMSO-d6) 12.19 (1H, br s), 8.32 (2H, m), 8.13 (1H, s), 7.78 (1H, d), 7.48 (1H, d), 7.23 (1H, dd), 4.31 (2H, q), 1.30 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[O:21]1[C:17]([C:13]2[CH:12]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)=[CH:18][N:19]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(-c3cnco3)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(-c3cnco3)c2)cn1
Yield: 88.6 %

Procedure:
A solution of 5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (0.092 g, 0.324 mmol) in MeOH (10 mL) was treated with 10% Pd/C (50% wet, 0.034 g, 0.032 mmol) and hydrogenated (1 atm) for 5 h. The solid was removed via filtration through diatomaceous earth and the filtrate concentrated to dryness to afford 5-((2-(oxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (73 mg, 89%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.46 (d, J=5.7 Hz, 1H), 7.84 (d, J=2.9 Hz, 1H), 7.76 (s, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 6.86 (dd, J=5.7, 2.5 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.06 (s, 2H); MS (ESI) m/z: 255.1 (M+H+).
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[NH4+].[N+:6]([O-:9])([O-:8])=[O:7].[K+].[N+]([NH:14][C:15]([NH2:17])=[NH:16])([O-])=O.[N+:18]([O-:21])([OH:20])=[O:19].[N+]([O-])(O)=O.[CH2:26]([NH2:29])[CH2:27][NH2:28].[N+](C1C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1C)([O-])=O>>[N+:1]([O-:4])([O-:3])=[O:2].[NH4+:6].[N+:18]([O-:21])([OH:20])=[O:19].[N+:6]([O-:9])([OH:8])=[O:7].[CH2:26]([NH2:29])[CH2:27][NH2:28].[N+:1]([O-:4])([OH:3])=[O:2].[NH2:16][C:15]([NH2:17])=[NH:14]
Reactant: N=C(N)N[N+](=O)[O-]
Agent: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: NCCN
Product: N=C(N)N

Procedure:
U.S. Pat. No. 4,421,578 by Voreck, Jr., discloses an explosive mixture containing ammonium nitrate, potassium nitrate, nitroguanidine and ethylenediamine dinitrate. This composition was developed for explosive applications with an intent to replace TNT (2,4,6-trinitrotoluene). The eutectic formed when ammonium nitrate, ethylene diamine dinitrate and guanidine nitrate are mixed in the disclosed proportion has a melting temperature below 100° C. Propellant mixtures with such a low melting point are not suitable for applications such as automobile airbag inflators where temperature stability in excess of 107° C. is frequently required.
Reaction SMILES: Br[CH:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH2:3]1.Cl.[NH:14]1[CH:18]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:16]=[CH:15]1>>[NH:14]1[CH:18]=[C:17]([CH2:19][C:20]2[S:21][C:2]3[CH2:3][S:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[C:11]=3[N:22]=2)[N:16]=[CH:15]1
Reactant: O=C1c2ccccc2SCC1Br
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: c1ccc2c(c1)SCc1sc(Cc3c[nH]cn3)nc1-2

Procedure:
Starting compounds: 3-bromothiochroman-4-one, 4-imidazolyl thioacetamide hydrochloride
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:19]=1.[N+]([O-])(O)=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:21])[C:11]3[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:19]=1
Reactant: CSc1ccc2c(c1)C=Cc1ccc(C=O)cc1S2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc2c(c1)C=Cc1ccc(C=O)cc1S2=O
Reaction time: 0.5 h

Procedure:
Dissolve 8-methylthiodibenzo[b,f]thiepin-3-carboxaldehyde (5 mmole) in methylene chloride (100 ml); and while cooling the solution in an ice-bath, add a 1M solution of 90% nitric acid in methylene chloride (5 ml). Monitor the reaction mixture by tlc after 30 minutes, and add the nitric acid solution in small increments until starting material has disappeared. Treat the reaction mixture with sodium bicarbonate solution to remove acidic substances. Dry the organic solution, evaporate to dryness, and purify the title product by column chromatography on silica gel using 1:4 ethyl acetate/toluene for elution.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].O.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33]([OH:36])(=[O:35])=[O:34]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33]([O-:36])(=[O:35])=[O:34]
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 g of clopidogrel free base having an optical purity of 99.3% ee which was prepared by the method similar to that disclosed in International Patent Publication No. WO 02/59128 was dissolved in 100 ml of ethyl acetate, and a solution containing 34.8 g of 2-naphthalenesulfonic acid monohydrate dissolved in a mixture of 150 ml of ethyl acetate and 5 ml of water was added thereto dropwise over a period of 30 minutes. Then, the mixture was stirred at room temperature for 12 hours, and then, at a temperature ranging from 0 to 5 for 4 hours. The precipitates formed were filtered, washed with 30 ml of ethyl acetate and dried at 50° C., to obtain 71.6 g of the title compound (yield: 87%) as an white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].C(OC(=O)COC(C)C)C.C(OC1C=CC(C=O)=CC=1OC)C1C=CC=CC=1.[CH3:49][C:50]1[CH:51]=[C:52]([C:57]2[S:58][C:59]([CH3:65])=[C:60]([CH2:62][CH2:63]O)[N:61]=2)[CH:53]=[C:54]([CH3:56])[CH:55]=1.COC(=O)CC(=O)C(Br)C.CC1C=C(C=C(C)C=1)C(N)=S.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:63][CH2:62][C:60]2[N:61]=[C:57]([C:52]3[CH:51]=[C:50]([CH3:49])[CH:55]=[C:54]([CH3:56])[CH:53]=3)[S:58][C:59]=2[CH3:65])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: Cc1cc(C)cc(-c2nc(CCO)c(C)s2)c1
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC(C)C
Agent: CCOC(=O)COC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3cc(C)cc(C)c3)sc2C)c(OC)c1)OC(C)C

Procedure:
In analogy to the procedure described in example 1 d], [rac]-3-(4-hydroxy-3-methoxy-phenyl)-2-isopropoxy-propionic acid ethyl ester [prepared from isopropoxy-acetic acid ethyl ester (Tetrahedron (1982), 38(17), 2733-9) and 4-benzyloxy-3-methoxy-benzaldehyde in analogy to the procedures described in examples 54 a]to c)] was reacted with 2-[2-(3,5-dimethyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 3,5-dimethyl-thiobenzamide (from 3,5-dimethyl-benzonitrile and NaSH, NH4Cl in N,N-dimethylformamide) in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(3,5-dimethyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-isopropoxy-propionic acid ethyl ester, which was farther saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(3,5-dimethyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-isopropoxy-propionic acid as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[CH:21][CH:20]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 3-bromo-2-chloropyridine (4.1292 g, 21.46 mmol), 4-(pyridin-2-ylamino)phenol (4.7912 g, 25.75 mmol), and cesium carbonate (2.082 mL, 25.75 mmol) in dimethyl sulfoxide at 80° C. to stir. Reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (2×10 mL), satd sodium chloride solution (2×10 mL), dried with magnesium sulfalte, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 0.5% to 4% methanol in DCM, to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 343.0 (M+1). IC50 (uM) 0.96.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:11](O)[C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2c(-c3ccc(Br)cc3)nc(-c3ccccc3Cl)n2O)cc[nH]1
Solvent: CO
Product: O=c1cc(-c2[nH]c(-c3ccccc3Cl)nc2-c2ccc(Br)cc2)cc[nH]1

Procedure:
Using the general procedure in Example 1 Step D, the intermediate of Example 3 Step A was treated with TiCl3 in methanol. 1H NMR (400 MHz, DMSO-d6): [M+1]+ 427.
Reaction SMILES: [ClH:1].[CH:2]1[C:16]2=[C:17]3[C:9]([C:10]4[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]([CH2:18][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[CH:3]=1.C1C2=C3C(C4C2=CC=C(C=O)C=4)=CC=CC3=CC=1.CC(N)(CO)CO>>[ClH:1].[CH:14]1[C:15]2=[C:10]3[C:9]([C:17]4[C:16]2=[CH:2][CH:3]=[C:4]([CH2:18][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[CH:5]=4)=[CH:8][CH:7]=[CH:6][C:11]3=[CH:12][CH:13]=1
Reactant: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Agent: CC(N)(CO)CO
Agent: Cl
Agent: O=Cc1ccc2c(c1)-c1cccc3cccc-2c13
Product: CC(CO)(CO)NCc1ccc2c(c1)-c1cccc3cccc-2c13

Procedure:
Using the reductive amination procedure outlined in 1D, 8-fluoranthenecarbaldehyde (1C) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave 2-((8-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 233°-234.5° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [C:1]([OH: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][C:18]([OH:20])=[O:19].[CH3:23][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:25]O>C1(C)C=CC=CC=1>[C:1]([O:22][CH2:23][CH:24]([CH3:25])[CH2:27][CH2:28][CH3:29])(=[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][C:18]([O:20][CH2:23][CH:24]([CH3:25])[CH2:27][CH2:28][CH3:29])=[O:19]
Reactant: CCCC(C)CO
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCC(C)COC(=O)CCCCCCCCCCCCCCCCC(=O)OCC(C)CCC
Temperature: 115 °C
Reaction time: 5 h

Procedure:
Octadecanedioic acid (ODDA, 5.00 g) was added to a 100-mL three-necked round-bottom flask. A Dean-Stark condenser was attached, followed by the addition of toluene to the ODDA and to the trap. 2-Methylpentyl alcohol (5.90 mL) was added to the ODDA mixture. The flask was immediately purged with nitrogen gas and p-toluenesulfonic acid (0.17 g) was added. The reaction mixture was heated to 115° C. and the reaction proceeded for 5 hours. Heat was then removed and the reaction mixture was allowed to cool to 60° C., at which point aqueous NaHCO3 (saturated) was added to achieve a neutral pH. After vigorous stirring, the organic layer was separated and dried over Na2SO4. The dried product was then subjected to a vacuum treatment to remove any residual solvent. A yellow oil was obtained. Analysis by 1H NMR provided the following chemical shifts: (400 MHz, CDCl3) δ 0.90-0.85 (m), 1.10-1.20 (m), 1.21-1.50 (m), 1.55-1.7 (t), 1.77 (o), 2.30 (t), 3.85 (dd), 3.95 (dd). Anaylsis by 13C NMR provided the following chemical shifts: (400 MHz, CDCl3) δ C, 173.947; CH, 32.366; CH2, 69.200, 35.691, 34.438, 29.701, 29.684, 29.641, 29.516, 29.319, 29.220, 25.095, 19.975; CH3, 16.885, 14.258.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([C:25](Cl)=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1>C1(C)C=CC=CC=1.O>[Br:17][C:18]1[CH:19]=[C:20]([C:25]([NH:1][C:2]2[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=2[CH3:8])=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: Cc1cc(Cl)nc(Cl)c1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
3-Amino-2,6-dichloro-4-methylpyridine (0.51 g, 2.85 mmol) was dissolved in toluene (35 mL) and pyridine (0.27 mL, 3.28 mmol) was added. 5-Bromo-2-chloro-3-pyridinecarbonyl chloride (0.80 g, 3.14 mmol) was then added dropwise over 30 min. The resulting mixture was stirred at room temperature for 1 h, diluted with water and extracted with toluene (2×). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting thick oil was triturated with CH2Cl2, and the white solid collected via suction filtration to give the title compound (0.41 g, 36% yield).