Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[CH3:17][C:18]([CH3:20])=O.O>ClCCCl>[CH:18]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)([CH3:20])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: [Na]
Solvent: O
Solvent: ClCCCl
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A suspension of 1-(4-nitrophenyl)piperazine (20 g, 190 mmol, 2 eq), sodium triaectoxyborohydride (41 g, 97 mmol, 2 eq), and acetone (18.8 g, 21.3 mL, 290 mmol, 3 eq) in DCE (400 mL) is stirred in a water bath at rt for 32 h. Water (100 mL) is slowly added (gas evolution) and resulting biphasic solution is stirred for 1 h. The phases are separated and the DCE extract is washed with water (2×100 mL). The combined aqueous extracts are extracted with DCE (2×50 mL), and the combined DCE extracts are filtered through a phase separation tube. The filtrate is concentrated on a rotary evaporator and the yellow oil obtained dried under vacuum for a further 2 h. The oily product obtained solidified on standing to provide 1-isopropyl-4-(4-nitrophenyl)piperazine as a yellow solid (16.5 g, 66% recovery). The product is used in the next step without further purification. LCMS Purity: 80% by ELS detection; LCMS-ESI (m/z): calcd for C13H19N3O2 249.1; [M+H]+ found, 250.3.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH3:15]>>[CH2:14]([S:16]([CH2:19][CH2:20][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:15]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CS(=O)(=O)CC
Product: CCS(=O)(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1.75 h
Yield: 69 %

Procedure:
A mixture of 64 g (0.34 mole) of diphenyl phosphine and 40.2 g (0.33 mole) of highly reactive, freshly distilled vinyl ethyl sulfone monomer was irradiated in the usual manner. To suppress polymer forming side reactions the temperature of the reaction mixture was kept below 5° C. by an ice-water bath and the u.v. irradiation was limited to 105 minutes. The adduct formed crystallized from the liquid mixture by the end of the reaction period. Consequently, the reaction mixture was filtered with suction to recover the crude, crystalline product, i.e. 2-ethylsulfonylethyl diphenyl phosphine. The crude, dried product (94 g, 94) was recrystallized from 670 ml methanol to yield 69 g (69%) of the compound (of unpleasant odor) as a white crystalline solid (Table 3).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Product: CC(=O)c1ccc(OCc2ccc(Sc3cncc(C#N)c3)cc2)c(C)c1O
Yield: 40.7 %

Procedure:
Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (0.86 g, 5.20 mmol) affords the title compound (787 mg, 41%): 1H NMR (d6-DMSO) δ 2.06 (s, 3H), 2.58 (s, 3H), 5.30 (s, 2H), 6.72 (d, J=9.0 Hz, 1H), 7.51-7.55 (m, 4H), 7.81 (d, J=9.0 Hz, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 2H), 8.91 (d, J=2.0 Hz, 1H), 12.85 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15]>>[CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:13]
Reactant: CC(=O)N(C)c1ccnc(Cl)c1
Reactant: CC(C)N1CCNCC1
Product: CC(=O)N(C)c1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of 4 g (22 mmol) N-(2-chloro-pyridin-4-yl)-N-methyl-acetamide and 2.8 g (22 mmol) 1-(2-propyl)-piperazine was heated to 120° C. for 24 h. The crude product was purified by flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate (0.1% NEt3) to yield after evaporation of the product fractions 2.5 g (41%) of the title compound as light brow oil. MS: (m/e): 277.2 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=1)([CH2:49][CH3:50])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:57][C:54]4[CH:55]=[CH:56][C:51]([CH:47]([CH2:49][CH3:50])[CH3:48])=[CH:52][CH:53]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCC(C)c1ccc(N)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(C(C)CC)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(4-sec-butyl-phenyl)-amine (TCI-US) to give the title compound. LC-MS (ES+) 796 [(M+H)+].
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([O:19]C)=[O:18])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([OH:19])=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
To methyl 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g) were added methanol (20 mL), THF (20 mL), and a 1 M aqueous sodium hydroxide solution (10 mL), followed by stirring at 60° C. for 16 hours. To the reaction mixture was added a 10% aqueous citric acid solution (20 mL), followed by extraction with ethyl acetate, and the organic layer was washed with brine. After dehydration over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, the obtained residue was added with diisopropylether, solidified, and collected by filtration. This solid was purified by silica gel column chromatography (chloroform/methanol=99/1-97/3) to obtain 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0.99 g).
Reaction SMILES: [OH-].[Na+].[O:3]([CH2:11][C:12](=[CH2:17])[C:13]([O:15]C)=[O:14])[CH2:4][C:5](=[CH2:10])[C:6]([O:8]C)=[O:7].C1(C=CC(O)=CC=1)O.Cl>O>[O:3]([CH2:4][C:5](=[CH2:10])[C:6]([OH:8])=[O:7])[CH2:11][C:12](=[CH2:17])[C:13]([OH:15])=[O:14]
Reactant: C=C(COCC(=C)C(=O)OC)C(=O)OC
Agent: Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Product: C=C(COCC(=C)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 15 g of sodium hydroxide in 135 g of water was added a mixture of 30 g (0.14 mol) of dimethyl 2,2'-[oxybis(methylene)]bis-2-propenoate and 60 mg of hydroquinone, which was followed by stirring at room temperature for 19 h. The reaction mixture was then brought to pH 1 with concentrated hydrochloric acid. The precipitated acid was filtered off, dissolved in 160 g of distilled water at 90° C., admixed with 10 g of active charcoal and then filtered hot. Cooling down to room temperature yielded 24.5 g (94%) of very pure 2,2'-[oxybis(methylene)]bis-2-propenoic acid having a melting point of 177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](O)=O)([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[S:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3s2)cc([N+](=O)[O-])c1
Temperature: 150 °C

Procedure:
3,5-Dinitrobenzoic acid (5.30 g) was mixed with 40 ml polyphosphoric acid and heated to 64° C. o-Aminothiophenol (2.5 ml) was added and reaction maintained to 150° C. over 0.5 hr period. The mixture was quenched with 600 ml ice-water, neutralized with KOH, cooled, and filtered. The product yield was 3.20 g, mp 73.5°-84.5° C.
Reaction SMILES: NC1C=CC(OC)=C2C=1C(=O)N(C)C2.[CH3:15][N:16]1[CH2:24][C:23]2[C:18](=[C:19]([N+:31]([O-])=O)[CH:20]=[CH:21][C:22]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]1=[O:34]>>[NH2:31][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:23]2[C:18]=1[C:17](=[O:34])[N:16]([CH3:15])[CH2:24]2
Reactant: CN1Cc2c(N3CCOCC3)ccc([N+](=O)[O-])c2C1=O
Agent: COc1ccc(N)c2c1CN(C)C2=O
Product: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O

Procedure:
The title compound was prepared according to the procedure for 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A) using 2-Methyl-4-(morpholin-4-yl)-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 208B). MS (ES+): m/z 248.23 (100) [MH+]; HPLC: tR=0.62 min (UPLC, analytical).
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].CS(O)(=O)=O.[NH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(N(CC)CC)C.O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.C(Cl)(Cl)Cl>[O:9]=[C:7]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)SC/C(=C/c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
0.95 g (4 mmol) of (E)-2-acetylthiomethyl-3-phenylpropenoic acid dissolved in 15 ml of anhydrous THF is placed in a round-bottomed flask fitted with a calcium chloride guard tube. The flask is cooled to approximately 0°-5° C. in an ice bath and 1.10 g (4 mmol) of benzyl β-alaninate methanesulphonate and 0.41 g (4 mmol) of triethylamine in 5 ml of chloroform, a solution of 0.54 g (4 mmol) of hydroxybenzotriazole monohydrate in 5 ml of THF and a solution of 0.83 g (4 mmol) of dicyclohexylcarbodiimide in 5 ml of chloroform are successively added with stirring. The mixture is allowed to return to room temperature and is stirred for 6 hours.
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]2>CCCCCC>[CH3:1][O:21][C:20](=[O:22])[CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[CH:15]=1)[CH3:23]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Yield: 89.5 %

Procedure:
To a solution of methanol (2100 ml) and sulphuric acid (84 ml) was added 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid (420 grams). The reaction mixture was refluxed for 6 Hours. Methanol (1000 ml) was distilled, and the cooled reaction mass was poured onto ice water to yield crude 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methyl ester which was filtered, dried and recrystallized using a mixture of ethyl acetate:hexane to yield pure product (400 grams, 89.5% yield) as a white fluffy powder with a melting point of 89.5-92° C. The pure product was characterized using 1H NMR spectroscopy in CDCl3 δ 1.60 (d, 3H, CH3), 3.70 (s, 3H, Ester), 3.88 (q, 1H, CH), 5.36 (bs, 1H, OH), 7.08 (m, 2H, Ar), 7.48 (m, 1H, Ar), 7.65 (m, 3H, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([NH2:22])[CH:20]=[CH2:21]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:19][CH:20]=[CH2:21])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: C=CCN
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Solvent: CCO
Product: C=CCNc1nc(-c2ccccc2)ncc1C(=O)OCC

Procedure:
A mixture of 5 g. (0.019 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 2.2 g. (0.038 mole) of allylamine in 150 ml. of ethanol was refluxed 3 hours. At this point, the solution was concentrated to 30 ml. and chilled. A yellow crystalline solid formed and was filtered off to give 4-(2-propenylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester--m.p. 49°-54° C. This compound was used in the next step directly without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:6]1[CH3:21])[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([CH3:21])=[C:7]2[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCCCn1c(C)c(-c2ccncc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 1-butyl-2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=O)=[CH:13][CH:12]=1>>[CH3:7][C:5]1[N:6]=[C:2]([CH3:1])[N:3]2[CH2:8][CH2:9][NH:10][CH:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=3)[C:4]=12
Reactant: Cc1ccc(CCC=O)cc1
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1ccc(CCC2NCCn3c(C)nc(C)c32)cc1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-p-tolyl-propionaldehyde. LC-MS: tR=0.57 min.; [M+H]+=270 g/mol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2.O>CC(N(C)C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([NH:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[C:29](=[O:30])[O:28][CH2:27]3)=[O:13])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: Nc1ccc2c(c1)COC2=O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)Nc1ccc2c(c1)COC2=O
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
1.7 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is dissolved in 25 ml of dimethyl acetamide and mixed under argon at −8° C. with 0.37 ml of thionyl chloride. After 20 minutes of stirring at −3 to +3° C., 700 mg of 5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4), and after the solvent is concentrated by evaporation and after chromatography of the crude product on silica gel with hexane/ethyl acetate (80:20), 1.5 g of 5-[4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-phthalide is obtained as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14]O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
Combine (3-nitrophenyl)acetic acid (20.0 g, 110 mmol) and anhydrous methanol (125 mL). Add 7 drops of concentrated sulfuric acid. Heat to 50° C. After 14 hours, cool to ambient temperature. Evaporate in vacuo to give a residue. Partition the residue between water and diethyl ether. Separate the organic layer and extract with aqueous saturated sodium bicarbonate solution and brine. Dry the organic layer over MgSO4 and filter. Slowly evaporate to give methyl (3-nitrophenyl)acetate. 1H NMR (CDCl3) δ 8.17 (d, 1 H, J=1.1 Hz), 8.14 (dd, 1 H, J=1.0, 7.7 Hz), 7.63 (dd, 1 H, J=1.1, 7.7 Hz), 7.52 (t, 1 H, J=7.7 Hz), 3.75 (s, 2 H), 3.73 (s, 3 H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][N:26]=[C:25]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:25]2[C:24]3[C:28](=[C:20]([F:19])[CH:21]=[CH:22][CH:23]=3)[NH:27][N:26]=2)[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=1
Reactant: Nc1n[nH]c2c(F)cccc12
Reactant: Clc1ccccc1-c1nc(Cl)c2cccnc2n1
Product: Fc1cccc2c(Nc3nc(-c4ccccc4Cl)nc4ncccc34)n[nH]c12

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, Rt 3.04 min; 1H NMR (DMSO, 500 MHz): δ 13.67 (1H, s), 11.40-11.25 (1H, bs), 9.35-9.25 (2H, m), 7.95 (1H, m), 7.80-7.47 (5H, m), 7.35(1H, m), 7.15 (1H, m); MS (m/z), MH+ 391.1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[F:19].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[F:19])[C:20]1[N:25]=[CH:24][C:23]([N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)=[CH:22][N:21]=1
Reactant: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (300 mg) is dissolved in toluene (5 ml) and tris(dibenzylideneacetone)dipalladium (48 mg), 2-(di-tert-butylphosphino)biphenyl (62 mg), sodium tert-butoxide (75 mg) and morpholine (68 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (176 mg). MS (m/z): 583 [M+H]+
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][C@H:18]([NH:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH2:17]3)[CH:12]=1)[C:6](OC)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:29][C:27]([F:28])([F:30])[S:24]([NH:23][C@@H:18]1[CH2:17][C:16]2[C:20](=[CH:21][CH:22]=[C:14]([CH2:13][C:11]3[CH:12]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:4]=[C:5]([CH2:6][OH:7])[CH:10]=3)[CH:15]=2)[CH2:19]1)(=[O:26])=[O:25]
Reactant: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(F)(F)F)C3)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-methyl 3-(trifluoromethyl)-5-((2-(trifluoromethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)benzoate (0.135 mmol, 65 mg) in THF (1.5 mL) at 0° C. was added Lithium aluminium hydride (0.405 mmol, 15.37 mg). The whole was stirred at 0° C. for 4 h before the reaction mixture was quenched by the addition of 2N HCl & diluted with DCM. The organics were separated/dried using a hydrophobic frit before being concentrated to dryness and the residue purified by preparative HPLC to give a clear film (29 mg, 47.4%). MS (ESI): m/z [M+NH4]+ 471.5
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: OCCCc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CCCBr)c1
Reaction time: 3 h
Yield: 73 %

Procedure:
Compound 12-1 (9.00 g) was dissolved in methylene chloride (80 ml), triphenylphosphine (12.8 g) and N-bromosuccinimide (8.63 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (200 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (8.59 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[NH2:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[C:12]([Cl:11])[CH:13]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(N)cc2Cl)cc1F

Procedure:
2.00 g (14.4 mmol) of 2,4-difluorobenzonitrile, 2.06 g (14.4 mmol) of 3-chloro-4-hydroxyaniline and 3.97 g (28.8 mmol) of potassium carbonate in 20 ml of acetonitrile are heated at RF for one hour. Ethyl acetate is added, the mixture is filtered and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60), giving the product which is a regioisomer mixture with a ratio of 62:38.