Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH2:32][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[C:4]([CH3:18])=[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:2]3[CH3:1])=[CH:12][CH:13]=1
Reactant: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(O)cc3)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1,3-dimethyl-2-phenyl-1H-indol-4-yl)-phenol (0.300 g, 0.957 mmol) was reacted with K2CO3 (0.172 g, 1.244 mmol) and methyl bromoacetate (0.190 g, 1.244 mmol) in acetone (5 ml) to give the product (0.287 g, 0.745 mmol, 78%) as a white solid, mp 110-112° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]([CH3:28])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19](C(OC)=O)[C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.CO>[C:3]([O:7][C:8]([N:10]([CH3:28])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: COC(=O)C(C(=O)OC)c1cccc(CCN(C)C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cccc(CCN(C)C(=O)OC(C)(C)C)c1
Temperature: 22 °C

Procedure:
To 429 μL (10.6 mmol) of methanol was slowly added 85 mg (2.1 mmol) of sodium hydride (60% dispersion in mineral oil). This mixture was then added to a separate solution of 387 mg (1.06 mmol) of dimethyl 2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)malonate in 5 mL of tetrahydrofuran. The resulting solution was refluxed for 2 h then cooled to 22° C. An additional 85 mg of NaH in 429 ml of methanol was added and the solution was again heated to reflux for about 16 h. The solvent was evaporated and the residue partitioned between saturated NH4Cl and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1OCOCO1.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCCl.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][S:11](=[O:12])(=[O:13])[NH:14][CH2:15][C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C1OCOCO1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CNS(=O)(=O)C2
Temperature: 35 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a mixture of (4-nitrophenyl)methanesulfonamide (864 mg, 4.0 mmol) and s-trioxane (120 mg, 4.0 mmol) in 1,2-dichoroethane (10 mL) was added trifluoromethanesulfonic acid (1.5 mL), followed by the addition of trifluoromethanesulfonic anhydride (1.5 mL, 4.0 mmol). The reaction mixture was stirred at 35° C. for 2 hours and refluxed overnight. The mixture was then diluted with dichloromethane (100 mL) and washed with water (100 mL) and brine (50 mL). The solvents were evaporated and the residue was purified by Prep-HPLC to give 6-nitro-3,4-dihydro-1H-benzo[d][1,2]thiazine 2,2-dioxide (210 mg, 23%) as a gray solid. MS (ES+) C8H8N2O4S requires: 228, found: 229 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:15]=2[C:16]([OH:18])=O)[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Si:31]([O:38][CH2:39][C@@H:40]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][NH:41]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>>[Si:31]([O:38][CH2:39][C@@H:40]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][N:41]1[C:16]([C:15]1[CH:19]=[C:20]([CH:21]=[CH:22][C:14]=1[C:10]1[N:11]([CH3:13])[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:18])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Yield: 87.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (Intermediate 281B, 170 mg, 0.42 mmol) and (S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline (237 mg, 0.85 mmol) were converted to the title compound (248 mg, 87%). MS(ESI+) m/z 675 (M+H)+.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OC)(OC)OC>>[CH3:10][O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCCCC1
Reactant: COC(OC)OC
Product: COC1=CCCCCCC1
Yield: 75.2 %

Procedure:
In the presence of 0.2 g of paratoluenesulfonic acid, 16.5 g (0.13 mol) of cyclooctanone and 16.5 g (0.15 mol) of trimetyl orthoformate were stirred at room temperature for four hours. The resultant mixture was heated at 100° C. for 14 hours. The vacuum distillation of the mixture gave 13.7 g (75% yield) of 1-methoxycyclooctene having a boiling point of 83° to 88° C./27 mmHg.
Reaction SMILES: C(O[NH:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:16]=[C:14]([I:15])[C:13]([O:17][C:18]2[CH:25]=[C:23]([I:24])[C:22]([OH:26])=[C:20]([I:21])[CH:19]=2)=[C:11]([I:12])[CH:10]=1)(C)(C)C.[Na+].[Cl-]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:10]=[C:11]([I:12])[C:13]([O:17][C:18]2[CH:19]=[C:20]([I:21])[C:22]([OH:26])=[C:23]([I:24])[CH:25]=2)=[C:14]([I:15])[CH:16]=1
Reactant: CC(C)(C)ON[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
30 mg of N-(tert-butoxy)-L-thyroxine-catalase conjugate (10 mL of 3.0 mg/mL solution in 10 mM potassium phosphate buffer, pH 7) is attached to the latex polymer particles prepared according to Example 1, particle size 0.069 μm, following the procedure of Example 7 except that the reaction is performed at 40° C. in the absence of NaCl.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[H-].[Na+].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:18]([O:17][C:16]([N:15]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][N:6]2[C:2]=1[CH3:1])[S:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:33])=[O:32])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccc(C(F)(F)F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(N(C(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2)nc2ccc(C(F)(F)F)cn12
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To a solution of compound 10-E (0.063 g, 0.2 mmol) in DMF (1 mL) at 0° C. was added 95% NaH (0.012 g, 0.5 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.053 g, 0.3 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H2O and the solution was extracted with ethyl acetate. After separation of the organic and aqueous layers a sufficient amount of water was added to remove any dissolved DMF from the organic layer. The organic layer was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 10-F as a white solid (0.066 g, 72%); MS m/z (M+H+) 456.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(Cl)Cl>[C:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of 35.28 g (105.5 mmole) methyl (triphenylphosphoranylidene)acetate in 70 mL methylene chloride was added to a solution of 11.36 g (52.76 mmoles) of (7) in 20 mL methylene chloride. After 2 h at room temperature, the solution was concentrated in vacuo to remove most of the solvent and the residue was diluted with ether. The solid was removed by filtration and the filtrate was concentrated and the residue chromatographed (Flash, hexane-ethyl acetate 7:3). The product fraction amounted to 10.7 g of a colorless oil (8).
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:9][CH2:10][CH3:11])(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O>[N:20]([CH2:6][CH:7]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][O:9][CH2:10][CH3:11])=[N+:21]=[N-:22]
Reactant: CCOCC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(tert-butoxycarbonyl)amino]-3-ethoxypropyl methanesulfonate (1.6 g, 5.4 mmol) in DMF (20 mL) was added sodium azide (1.10 g, 16.2 mmol) and then the reaction mixture was heated to 50° C. After 24 hours, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and the resulting residue was purified via silica chromatography to give tert-butyl (1-azido-3-ethoxypropan-2-yl)carbamate. MS ESI calc'd. for C10H21N4O3 [M+H]+ 245. found 245.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([OH:36])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:36][CH2:44][C:45]#[N:46])[CH:3]=1
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4O)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OCC#N)nccc3c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the crude material from Step 1 was added DMF (1.5 ml) followed by cesium carbonate (175 mg, 0.538 mmol) and bromoacetonitrile (24.99 μl, 0.359 mmol). The resulting mixture was stirred at 60° C. overnight affording clean conversion to desired product according to LC-MS. The mixture was filtered through Celite with the aid of DCM and the filtrate dried under reduced pressure. m/z (ESI) 577.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7].[S:36](N)([NH2:39])(=[O:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:39][S:36]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(=[O:38])=[O:37]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)NCCCNS(N)(=O)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide (100 mg) in DMF (3 mL), sulfamide (Aldrich, 62 mg) and potassium carbonate (50 mg) were added and the mixture was stirred at 100° C. for 6 hrs. The solvent was removed under reduced pressure and the residue was portioned between EtOAc and water. The organic layer was separated and dried with sodium sulfate. The solvent was removed and the residue was chromatographed on an ISCO machine (70-100% EtOAc/Hexanes) to give a white solid. 25 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(C)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Dimethylamine were converted to yield [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-dimethyl-amine as white semisolid, MS: 391 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]#[N:26])=[CH:7]2.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(Cl)c23)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(Cl)c23)C1

Procedure:
To (S)-tert-butyl 3-((8-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (120 mg, 0.32 mmol) in MeOH (50 mL) was added NH2NH2—H2O (5 mL). The resulting mixture was heated to reflux for 2 hours and then cooled and concentrated in vacuo to give the title compound as a yellow solid, which was used without further purification (130.3 mg, 100%). ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH:23]1([CH2:29][CH2:30][C:31](O)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[CH:23]1([CH2:29][CH2:30][C:31]([O:1][C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Reactant: O=C(O)CCC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)CCC3CCCCC3)cn2)cc1
Yield: 57.5 %

Procedure:
3.00 g (10.0 mmol) of 5-hydroxy-2-(4-octyloxyphenyl)pyrimidin, 1.56 g (10.0 mmol) of 3-cyclohexylpropionic acid, 2.06 g (10.0 mmol) of N,N-dicyclohexylcarbodiimide and 0.1 g of 4-N,N-dimethylaminopyridine in 80 ml of dichloromethane are stirred at room temperature for 18 hours. Insoluble constituents are then filtered off, the mixture is evaporated, and the residue is purified by chromatography (silica gel/dichloromethane) and recrystallization from hexane, giving 2.52 g of 2-(4-octyloxyphenyl)pyrimidin-5-yl 3-cyclohexylpropionate. ##STR12##
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[Br:18][C:19]1[N:20]=[C:21]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cn1cc(B(O)O)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Product: Cn1cc(-c2cccc(Br)n2)ccc1=O
Temperature: 80 °C

Procedure:
A flask was charged with (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid (80 mg, 0.52 mmol), potassium carbonate (217 mg, 1.57 mmol), and 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (19 mg, 0.026 mmol) and evacuated and purged with argon (5×). 2,6-Dibromopyridine (130 mg, 0.55 mmol) was placed into a separate flask and evacuated and backfilled with argon (3×). Degassed dimethylformamide (3.6 mL) was added to the vial containing 2,6-dibromopyridine and the solution was transferred to the flask containing the remainder of the reactants. The mixture was heated at 80° C. overnight, then cooled to room temperature, taken up in water, and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified via silica gel chromatography (0-5% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:20])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Temperature: 90 °C
Yield: 97.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(pyridin-2-ylamino)phenyl]propionamide (190 mg, 0.69 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (186 mg, 0.78 mmol) and DIPEA (380 μL, 2.22 mmol) in n-butanol (1.5 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded into an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo to afford the title compound as an orange/brown oil (263 mg, 97%). LCMS (Method C): RT 1.67 min [M+H]+ 393.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:34](O)=[O:35]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][C:13]3[C:15]([CH:34]=[O:35])=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2nc3ccc(OC)cc3[nH]2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1ccc(-c2nc3ccc(OC)c(C=O)c3[nH]2)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
A mixture of 4-(6-Methoxy-1H-benzoimidazol-2-yl)-benzoic acid methyl ester (1.50 g, 5.3 mmol), hexamethylenetetramine (1.50 mg, 10.60 mmol) and trifluoroacetic acid (12 mL) was stirred in a closed vessel under an argon atmosphere at 130° C. for 3 h. The resultant brown solution was poured onto 250 mL of crushed ice. The mixture was extracted with, chloroform-ethanol 95:5 (2×0.100 mL). The combined organic layers were dried (Na2SO4), and evaporated. The solid residue was purified by column chromatography over silica (Kieselgel 60) using chloroform as the eluent to give title compound (350 mg, 1.13 mmol, 21%) yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:41]=[CH:40][C:12]([O:13][CH2:14][C@@H:15]([OH:39])[CH2:16][NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]3[CH:38]=[CH:37][C:27]([O:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:11][C:10]=1[S:42]([CH2:44][CH2:45][CH2:46][CH3:47])=[O:43])C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:44]([S:42]([C:10]1[CH:11]=[C:12]([CH:40]=[CH:41][C:9]=1[OH:8])[O:13][CH2:14][C@@H:15]([OH:39])[CH2:16][NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:25]=[CH:26][C:27]([O:28][C:29]([CH3:35])([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:37][CH:38]=2)[CH2:20][CH2:19]1)=[O:43])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCS(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(OC(C)(C)C(=O)OCC)cc3)CC2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCS(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(OC(C)(C)C(=O)OCC)cc3)CC2)ccc1O

Procedure:
A solution of 0.720 g of ethyl trans-2-{4-[4-({(2S)-3-[4-(benzyloxy)-3-(butylsulfinyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]phenoxy}-2,2-dimethylacetate (1.08 mmol) in trifluoroacetic acid (12 ml) is heated at 60° C. for 3 hours. The solvent is evaporated and the residue is treated with a sodium bicarbonate solution and ethyl acetate. The organic phase is separated, dried, filtered and evaporated under vacuum. The product thus obtained is purified by flash chromatography, elution being carried out with a methylene chloride/methanol/aqueous ammonia (9/1/0.1) mixture. The title product is obtained in the form of a solid (0.31 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.Cl.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O.C(OCC)(=O)C>[N:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc2cccnc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc2cccnc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
1 g (1.9 mmol) of benzotriazol-1-yloxytris(pyrrolidine)phosphonium hexafluorophosphate is added, with stirring and under nitrogen, to a suspension of 0.5 g (1.74 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, obtained in step 11.1, in 10 ml of dry dimethylformamide. After 5 minutes, 0.4 g (1.83 mmol) of 7-aminoquinoline hydrochloride (WO 2003/049702) and 0.9 g (7 mmol) of diisopropylethylamine are added. After stirring for 2 hours at room temperature and for 2 hours at 60° C., the reaction medium is poured into 100 ml of water and 50 ml of ethyl acetate. After separation of the phases by settling and extraction of the aqueous phase, the organic phases are combined, washed with water and dried over sodium sulfate. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and acetone. The solid obtained is recrystallized from isopropyl alcohol. 0.26 g of solid is obtained.