Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CC(C)=O.[OH-].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19]>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH:17]2[CH:1]([OH:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:4]2)=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1Oc2ccccc2C1O

Procedure:
To a solution of 15.3 g. (0.125 mol.) of salicylaldehyde in 100 ml. of acetone was added 7.0 g. (0.125 mol.) of potassium hydroxide dissolved in a minimum amount of water. α-Bromo-p-chloroacetophenone (29.16 g., 0.125 mol.) was added dropwise with stirring and cooling (ice bath). After addition, the reaction mixture was stirred at 25° for 12 hours. The precipitate was collected by filtration, washed with water and combined with the residue remaining after concentration of the filtrate to give 2-(4-chlorobenzoyl)-3-hydroxycoumaran which was immediately dehydrated in the presence of p-toluenesulfonic acid to yield 2-(4-chlorobenzoyl)benzofuran.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:25])=[O:5]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was added over about 5 minutes. The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer was washed with 3N HCl, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give pure compound (32 g, 81%): mp 48°-49° C.; 1H NMR CDCl3 δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ -72.0. EI GC-MS M+=242.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH:5]2[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][CH:4]2[C:3]1=[O:13].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>ClCCCl>[C:21]([O:1][N:2]1[C:6](=[O:7])[CH:5]2[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][CH:4]2[C:3]1=[O:13])(=[O:24])[CH:22]=[CH2:23]
Reactant: CC1CCC2C(=O)N(O)C(=O)C2C1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=CC(=O)ON1C(=O)C2CCC(C)CC2C1=O
Temperature: 25 °C
Yield: 90.4 %

Procedure:
Next, 10.07 g (0.055 mol) of N-hydroxy-4-methylhexahydrophthalimide, 15 ml (0.11 mol) of triethylamine, and 50 ml of 1,2-dichloroethane were poured in a 100 ml flask. Then, 7.2 ml (0.090 mol) of acrylyl chloride was slowly dropped therein at a room temperature under nitrogen with stirring. After the dropping, a mixture thus prepared was reacted for one hour at a room temperature. A reaction mixture was washed with water so as to separate an organic layer therefrom. Then, the organic layer was washed with a 5% sodium hydrogen carbonate aqueous solution. The organic layer separated from the 5% sodium hydrogen carbonate aqueous solution was dried with magnesium sulfate, and then a solvent was removed from the organic layer. 11.8 g of N-(acryloyloxy)-4-methylhexahydrophthalimide (viscous liquid of dark yellow color) was thereby obtained. N-(acryloyloxy)-4-methylhexahydrophthalimide is represented by the following formula (120):
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([OH:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[OH:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: NCCc1ccccc1
Reactant: CC(O)c1ncnc(Cl)c1I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-hydroxy-ethyl)-5-iodopyrimidine (1.4 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C=O>[C:40]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]=[C:24]([C:22]([NH:21][C@@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]3[NH:14][C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)=[O:13])=[O:23])[S:25][C:26]=2[CH2:27]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@H]1CCCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (100 mg) obtained in Example 34 was dissolved in N,N-dimethylformamide (3 mL), triethylamine (84 μl) and acetic anhydride (29 μl) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue for partitioning the mixture. The resultant organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=100:3) to give the title compound (86 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[S:11][CH2:12][CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1OC>CO>[NH2:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1[NH:14][CH2:13][CH2:12][S:11][C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1
Reactant: NCCSc1cccc(CN2CCCCC2)c1
Reactant: COc1c(N)c(=O)c1=O
Solvent: CO
Product: Nc1c(NCCSc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
The crude amine prepared in Step E (1.4 g, 4.05 mmoles) in 40 mL of methanol was added to a suspension of 1-amino-2-methoxycyclobutene-3,4-dione (0.515 g, 4.05 mmoles) in 100 mL of methanol. The mixture was stirred for 20 hours at ambient temperature and then filtered to give 0.8136 g of product. A second crop was obtained from the concentrated mother liquor and the combined lots were recrystallized from methanol to yield 0.786 g (56%) of the title compound, m.p. 228°-230° (dec.).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.Cl[Si:12]([CH3:27])([CH3:26])[CH:13]1[C:21]2[S:22][C:23]([CH3:25])=[CH:24][C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2>CCOCC.CCCCCC>[C:1]([NH:5][Si:12]([CH3:26])([CH3:27])[CH:13]1[C:21]2[S:22][C:23]([CH3:25])=[CH:24][C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(s1)C([Si](C)(C)Cl)c1ccccc1-2
Reactant: CC(C)(C)N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc2c(s1)C([Si](C)(C)NC(C)(C)C)c1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.93 mL (0.0089 mol) of tert-butylamine in 30 mL of ether was treated dropwise with 5.55 mL (0.0089 mol) of 1.6M BuLi in hexane at −30° C. The reaction mixture was stirred at r.t. for 3 h and the resulting suspension was treated with a solution of 2.47 g (0.0088 mol) of chloro(dimethyl)(2-methyl-8H-indeno[2,1-b]thiophen-8-yl)silane in 10 mL of ether at −70° C. The resulting suspension was allowed to warm to r.t. and was stirred overnight. The solution was separated from LiCl and evaporated. The residue was treated with 60 mL hexane, the solution was isolated and evaporated. Yield 1.98 g (71%) of crude product as red oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].BrN1[C:30](=[O:31])CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:31][CH3:30])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOc1nc(N)c2ncn(Cc3cccc(C#N)c3)c2n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(C#N)c3)c2n1
Reaction time: 1 h
Yield: 41.2 %

Procedure:
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (7) (1.0 g) was suspended in acetonitrile. N-Bromosuccinimide (1.0 g) was added in small portions over 10 minutes. After stirring for 1 hour, the mixture was diluted with ethyl acetate, washed with 10% aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4 and evaporated to dryness under vacuum. The crude 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (8) was dissolved in methanol (50 mL) and 50% aqueous KOH solution (1 mL) was added. The mixture was heated under reflux for 3 hours and then concentrated under vacuum. The product was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: 0-10% MeOH in ethyl acetate) gave 3-((6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (9) (0.45 g) as a pinkish solid.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O.[OH-].[K+]>>[CH3:17][C:16]1([CH3:20])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(N)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCC1=NC(C)(C)CO1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
64 g (320 mmoles) of dodecanoic acid and 61.1 ml (640 mmoles) of 2-amino-2-methylpropanol was placed in a two neck flask equipped with a vigreux column, distillation condenser and a thermometer. The temperature of the reaction mixture was slowly brought to 180° C. and maintained there for 9 hours. After cooling, a 10% alcoholic KOH solution (2 g, 3.6 mmoles) was added and the reflux was continued at 180° C. for 4 hours. The excess 2-amino-2-methylpropanol was distilled at aspirator pressure (86°C./ 18 mm). When the vapor temperature reached 103° C., the distillation was discontinued and the residue was taken in petroleum ether and filtered. The filtrate was washed with dilute KOH, water, dried and concentrated. The oil was distilled at 120° C./ 1.2 mmHg to give 70.5 g (87%) of product.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30])(=O)=O>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Reactant: CS(=O)(=O)OCCN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncn(CCN3CCCC3=O)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (0.8 g, 3.5 mmol) in DMF (10 ml) was added NaH (0.28 g, 7 mmol) followed by the addition of 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (0.7 g, 3.5 mmol). The mixture was then stirred overnight at RT. Reaction was quenched with water (10 ml) and mixture extracted with ethyl acetate. Ethyl acetate layer was separated, dried over anhydrous sodium sulfate and evaporated to yield 0.5 g of methyl 5-methyl-4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as an oil (yield: 42.8%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[C:2]=[O:3].[CH3:13][CH:14]([CH3:37])[CH:15]([NH:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:22])[C:16]([O:18][CH3:19])=[O:17]>>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][C:2](=[O:3])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:25]4[S:24][C:23]([C:21]([NH:20][C@@H:15]([CH:14]([CH3:37])[CH3:13])[C:16]([O:18][CH3:19])=[O:17])=[O:22])=[N:27][CH:26]=4)=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 5-isocyanato-2,3-dihydro-1H-indene (0.599 mmol) and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ ppm 8.891 (s, 1H), 8.732-8.704 (d, 1H), 8.602 (s, 1H), 8.347 (s, 1H), 7.717-7.689 (d, J=8.4 Hz, 2H), 7.575-7.547 (d, J=8.4 Hz, 2H), 7.289 (s, 1H), 7.172-7.101 (m, 2H), 4.349-4.299 (t, J=7.2, 7.8 Hz, 1H), 3.681 (s, 3H), 2.859-2.770 (m, 4H), 2.328-2.204 (m, 1H), 2.054-1.952 (m, 2H), 0.965-0.923 (d, J=6.3 Hz, 6H); MS (ESI) m/z 491 (M−H), 493 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:25][CH2:24]2)[CH3:22])[C:9]([N+:37]([O-:39])=[O:38])=[C:8]([CH3:40])[NH:7][C:6]=1[NH2:41])=[O:4].ClC1C=CC=C(C(OO)=[O:50])C=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:18][CH2:19][CH2:20][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:25][CH2:24]2)[CH3:22])=[O:50])[C:9]([N+:37]([O-:39])=[O:38])=[C:8]([CH3:40])[NH:7][C:6]=1[NH2:41])=[O:4]
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCC(C)N1CCN(c2ccccc2OC)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)CCCC(C)N1CCN(c2ccccc2OC)CC1

Procedure:
This compound was prepared from 2-amino-1 4-dihydro-4-(2-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-pentylthio}phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester and m-chloroperbenzoic acid in the same manner as described for Example 2. 1H-NMR (CDCl3) δ 1.65(br s,4H); 2.02(m,2H); 2.42(s,3H); 2.49(m,2H); 2.71(s,4H); 2.98(m,2H); 3.12(s,4H); 3.61(s,3H); 3.86(s,3H); 5.76(s,1H); 6.68(s,2H); 6.84-7.01(m,4H); 7.27(m,4H); 7.81-7.86(m,1H). Mass spectrum: 598 (M+H).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 72.6 %

Procedure:
A mixture of intermediate (16) (0.025 mol) in methanol (250 ml) was hydrogenated at 50° C. overnight with Pd/C 10% (2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 7.7 g N-[4-(4-piperidinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 17).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH:53]=2)[NH:48][C:47]=1[C:63](O)=[O:64].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:56](=[O:57])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:53]=2)[NH:48][C:47]=1[C:63]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:64]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Cl)c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
HATU (0.119 g, 0.314 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.055 g, 0.209 mmol), 3-chloro-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.065 g, 0.209 mmol) and diisopropylethylamine (0.055 mL, 0.314 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.033 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 9.28 (br. s., 1H), 8.44 (t, 1H), 7.78 (br. s., 2H), 7.48 (d, 2H), 7.35-7.45 (m, 2H), 7.26-7.32 (m, 1H), 7.19-7.26 (m, 1H), 4.58 (d, 2H), 1.42 (s, 9H). ES MS: m/z 601 (M−1).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[C:4](OCC)=O)=[O:2].C[O-].[Na+].[N+:21]([NH:24][C:25]([NH2:27])=[NH:26])([O-:23])=[O:22]>CO>[N+:21]([NH:24][C:25]1[NH:27][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][N:26]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)C(C=O)Cc1cccc(OC)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Yield: 29.2 %

Procedure:
Ethyl 2-formyl-3-(3-methoxyphenyl)propionate (10 g) was added dropwise to a stirred and boiling mixture of sodium methoxide (from 1.15 g sodium) and nitroguanidine (25% wet, 5.5 g) in methanol (250 ml) and the mixture was heated under reflux for 20 hours and evaporated to dryness. The residue was dissolved in water (100 ml), the solution was extracted with ether and the aqueous phase was adjusted to pH 4: the solid which separated was recrystallised from ethanol to give 2-nitroamino-5-(3-methoxybenzyl)-4-pyrimidone (3.41 g, 29%), m.p. 178°-9°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10].[H-].[Na+].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[N:26][C:25]=1[CH2:36]I.O>CC(OC)(C)C>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[O:28][C:24]=2[CH3:23])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Reactant: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cccc(-c2nc(COCCCOCc3cccc(C)c3C(=O)O)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate are dissolved in 1.0 ml of MTBE, and 57 mg of sodium hydride (60% in mineral oil) are added. After gas evolution ceases, 446 mg of 5-methyl-2-m-tolyloxazol-4-ylmethyl iodide are added, and the suspension is stirred at RT overnight. Water is then added, and the solution is poured into a kieselguhr cartridge (VARIAN CHEM ELUT 1010). The product is eluted with MTBE and concentrated. The residue is dissolved without purification in DCM/TFA (3:1) and stirred at 40° C. for 5 h. The solution is concentrated and purified by prep. HPLC, resulting in 202 mg of 2-methyl-6-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)propoxymethyl]benzoic acid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CCC(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCNc1ccc(CCC(=O)O)cc1

Procedure:
A 4 g. sample of ethyl 4-(allylamino)hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:20]3[CH:19]=[C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:25]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH3:85])[CH2:24]4)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Br:90])(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([Br:90])[C:20]3[CH:19]=[C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:25]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH3:85])[CH2:24]4)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1
Reactant: CC(=O)Br
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(O)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(Br)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 386.2 %

Procedure:
9-(4-Chlorophenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenol (62.0 mg, 51.2 μmol) was dissolved in chloroform (2 mL), acetyl bromide (13 μmol, 172 μmol) was added, and the mixture was stirred at room temperature for 1 hours. After evaporation of the solvent, acetonitrile was added to the residue to allow crystallization to give 9-(4-chlorophenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-bromofluorene (63.9 mg, 50.2 μmol, 98%).