Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH3:41])=[CH:34]/[CH:35]=[CH:36]/[C:37]([CH3:40])([OH:39])[CH3:38])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH3:41])=[CH:34]/[CH:35]=[CH:36]/[C:37]([CH3:40])([OH:39])[CH3:38])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: C/C(=C\C=C\C(C)(C)O)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C/C(=C\C=C\C(C)(C)O)c1cccc(CCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 59(h), by reacting 410 mg (0.7 mmol) of (3E,5E)-6-{3-[2-(3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-phenyl}-2-methylhepta-3,5-dien-2-ol (prepared in a manner similar to Examples 53(a-g)) with 2 ml (2 mmol) of a tetrabutylammonium fluoride solution (1M in THF), a colourless oil is obtained (m=230 mg; Y=96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][CH:12]1[CH2:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:15][CH:16]([CH3:18])[CH2:17][CH:12]([CH3:11])[CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: CC1CNCC(C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CC(C)CN(c2ccc(Cl)cc2C#N)C1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 5-chloro-2-fluoro-benzonitrile (0.700 g, 4.499 mmol) in anhydrous DMF (8.0 mL) was added 3,5-dimethylpiperdine (0.713 g, 6.299 mmol) and cesium carbonate (4.30 g, 13.497 mmol). The reaction mixture was heated at 80 C for 2 h. Upon cooling to rt, water and ethylacetate was added. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. To the combined organic layer was added ether and the organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to give 1.15 g (96%) of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile as solid. LCMS 249(M+1)+. The compound was >98% purity and was hence used directly for the next step
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)ccc1O
Yield: 94.8 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid (100 g, 0.57 mol), 20 ml of conc. H2SO4 and 200 ml of dry methanol was heated under reflux for 22 hours. An additional 5 ml of conc. H2SO4 was then added and the solution heated for an additional 24 hours. The solvent was evaporated under reduced pressure and the resulting residue poured into aqueous saturated Na2CO3 and then extracted with CH2Cl2 (2×400 ml). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated to give the desired compound as a white solid (100.5 g, 94.8% yield), mp 44°-46° C. IR (nujol) 1680 (ester) cm-1. NMR (CDCl3) δ 10.60 (s, 1H, OH), 7.73 (d, 1H, JBC =3 Hz HC), 7.33 (d of d, 1H, JAB =9 Hz, HB), 6.87 (d, 1H, HA), and 3.92 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][C:23](=[O:25])[CH2:22][C@H:21]([CH3:26])[O:20]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3([OH:25])[CH2:22][C@@H:21]([CH3:26])[O:20][C@@H:19]([CH3:18])[CH2:24]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Product: C[C@@H]1CC(O)(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one. Brown solid. MS (m/e): 338.4 ([M+H]+, 100%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:43][C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=21
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4I)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 656.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH:25]=O.CO.[BH3-]C#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:25][C:24]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:22]([O:21][CH3:20])[CH:23]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 275 mg of 3,4,5 trimethoxybenzaldehyde in place of the benzaldehyde, 4 ml of methanol and 0.2 ml of acetic acid then the reaction medium is agitated at ambient temperature for 5 hours. Then 100 mg of NaBH3CN is added and the reaction medium is agitated at ambient temperature for approximately 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 95/05/0.33, 305 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [N+:1]([C:4]1[C:27]([F:28])=[C:26]([F:29])[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:10]=2)=[C:6]([F:30])[C:5]=1F)([O-:3])=[O:2].C(=O)([O-])[O-:33].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O.O>[OH:33][C:5]1[C:6]([F:30])=[C:7]([C:26]([F:29])=[C:27]([F:28])[C:4]=1[N+:1]([O-:3])=[O:2])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
43.8 g of 1-(4-nitro-2,3,5,6-tetrafluorophenoxy)-3-benzyloxy-4-nitrobenzene prepared as described in Example 12 (0.1 mol) are dissolved in a mixture of 200 ml of dimethyl sulfoxide and 30 ml of water in a three-neck flask fitted with reflux condenser and stirrer. 15 g of potassium carbonate (0.11 mol) and 10 g of potassium hydrogen carbonate (0.1 mol) are added in portions to the solution, and the mixture is then stirred at 80° C. for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 400 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated reaction product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([Br:15])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28]C(N)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(O)(C)C>[Br:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:28]=[CH:29][C:24]([N:20]4[CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[CH2:18][CH2:19]4)=[CH:25][CH:26]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: CN1CCCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)CC1

Procedure:
5-Bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 4-(4-methyl[1,4]diazepan-1-yl)phenylamine by method A1 with addition of isopropanol in addition. The product with the molecular weight of 419.34 (C18H19BrN4OS) was obtained in this way; MS (EST): 419, 421 (N+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH:10]([OH:23])[CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[NH2:12][CH2:11][CH:10]([OH:23])[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Product: NCC(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 2-(3-(dibenzylamino)-2-hydroxypropyl)isoindoline-1,3-dione (4.5 g, 11.25 mmol) in conc. HCl (50 mL) was stirred at 120° C. overnight. After cooling to room temperature, the mixture was filtered. And the filtrate was extracted with CHCl3. The aqueous layer was added aq. 30% NaOH until pH was above 7, then the solution was extracted with CH2Cl2, dried over Na2SO4 and concentrated to give yellow solid (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15]>>[CH3:1][O:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[O:15][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Product: COc1cc(OC)c2cc(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Yield: 75 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone: Yield 75% following procedure A.2; m.p. 131-132° C.; IR 2960, 1619, 1497, 1227, 1203, 1134, 1110 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 7.04 (s, 2H), 7.00 (s, 1H), 6.74 (s, 1H), 6.36 (d, J=1.8 Hz, 1H), 3.97 (s, 6H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 159.4, 156.7, 153.8, 153.7, 153.6, 138.4, 126.6, 113.5, 101.9, 98.7, 94.6, 88.5, 61.2, 56.4, 56.0, 55.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:30]([CH2:32][CH3:33])[CH3:31]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:30]([CH2:32][CH3:33])[CH3:31])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(C)Br
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Oc1cccc(-c2nc(-c3ccc(F)cc3)ncc2OC)c1
Yield: 70.1 %

Procedure:
1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine, 5.5 g of potassium carbonate, and 5.5 g of 2-bromobutane were added to 200 ml of acetone, and the resulting mixture was heated under reflux for 2 days. The solvent was distilled away under reduced pressure. The residue was washed with water, and then purified by column chromatography on silica gel, thereby obtaining 1.0 g of 2-(4-fluorophenyl)-4-[3-sec-butoxyphenyl)-5-methoxypyrimidine (Compound 50).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:8]([CH:9]([NH:13][CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(#N)C>[CH3:14][N:13]([CH:9]([C:8]1[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][CH:5]=[N:6][CH:7]=1)[CH:10]([CH3:12])[CH3:11])[C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNC(c1cncnc1C(F)(F)F)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
6 g (26 mmol) of 4-trifluoromethyl-5-[1-(N-methylamino)-2-methylpropyl]pyrimidine and 3.6 g (26 mmol) of potassium carbonate were dissolved in 150 ml of acetonitrile, and 4 g (26 mmol) of phenylacetyl chloride was dropwise added, followed by stirring at room temperature for 3 hours. To the reaction solution, 200 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were washed with n-hexane to obtain 7.7 g (yield: 85%) of N-methyl-N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)propyl]phenylacetamide as colorless transparent crystals (melting point: 106-109° C.).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[F:10][C:9]1[C:2]([N:14]2[CH2:15][CH2:16][CH:12]([F:11])[CH2:13]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: F[C@H]1CCNC1
Reactant: O=Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cccc(F)c1N1CCC(F)C1
Yield: 26.9 %

Procedure:
2,3-Difluorobenzaldehyde (1.0 g, 7.037 mmol) was taken up in dry dioxane (20 ml) in a tube and (S)-3-fluoropyrrolidine (627.1 mg, 7.037 mmol) and K2CO3 (676.4 mg, 10.56 mmol) were added and the mixture refluxed overnight. The reaction mixture was diluted with ethyl acetate, filtered, concentrated to dryness and purified on an ISCO system eluting with Hexane/ethyl acetate (10-100) to give 400 mg of 3-fluoro-2-(3-fluoropyrrolidin-1-yl) benzaldehyde.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[C:11]([Cl:14])[N:12]=[CH:13][C:8]=2[C:7](I)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:28]=1)[C:22](N(OC)C)=[O:23]>>[Br:16][C:17]1[CH:28]=[C:21]([C:22]([C:7]2[C:8]3[CH:13]=[N:12][C:11]([Cl:14])=[N:10][C:9]=3[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)=[O:23])[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: CC(C)(C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-tert-butyl-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 63) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a brown oil in 36% yield, 2.1 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]([NH:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:12][CH:11]=1>C(O)CCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]([NH:26][CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:31][CH2:32]3)=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Reactant: C=Cc1ccccn1
Solvent: CCCCO
Product: Fc1ccc(Cn2c(NC3CCN(CCc4ccccn4)CC3)nc3cncnc32)cc1
Yield: 15 %

Procedure:
A mixture of 1.93 parts of 2-ethenylpyridine, 5 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine and 80 parts of 1-butanol was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (15%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-9H-purin-8-amine; mp. 172.3° C. (compound 141).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:19]=3)=[N:11][C:12]([C:15](O)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:63][C:64]1([C:70]([OH:72])=[O:71])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.Cl>CN1C(=O)CCC1.C(#N)C.O.C(Cl)Cl.CO>[ClH:1].[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH:19]=3)=[N:11][C:12]([C:15]([NH:63][C:64]3([C:70]([OH:72])=[O:71])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)O)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Reactant: NC1(C(=O)O)CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)CCCCC3)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 1.49 g (3.1 mmol) of 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid in 15 mL of anhydrous NMP are added under argon 1.62 mL (9.3 mmol) of DIEA and 2.83 g (8.82 mmol) of TBTU. In parallel, a mixture of 421 mg (2.94 mmol) of 1-aminocyclohexanecarboxylic acid and 1.51 mL (6.19 mmol) of BSA in 15 mL of anhydrous acetonitrile is brought to 90° C. with stirring and under argon. After 2 hours, the medium dissolves completely and the solution is cooled to room temperature and then added to the solution of 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid activated with TBTU. After stirring for 2 hours at room temperature, 10 mL of aqueous 0.5N HCl solution are added and stirring is continued for 18 hours. The reaction medium is then poured into a mixture of 100 mL of 9/1 DCM/MeOH and 10 mL of water. After extraction, the aqueous phase is again extracted with 10 mL of a 9/1 DCM/MeOH mixture. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The residue is then purified by reverse-phase HPLC (RP18) using an aqueous 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile. After concentrating under reduced pressure and freeze-drying, 1 g of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride is obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:17][C@H:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]([NH:17][C@H:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH3:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N[C@@H](C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(N)cc1)N[C@@H](C)C(=O)OC(C)(C)C

Procedure:
Hydrogenate a solution of N-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl ester (20.0 g) (see Preparation 2, IA) in absolute ethanol (500 ml) in the presence of 10% palladium on carbon (1.5 g) at 50 psi in a Parr shaker apparatus. Remove the catalyst by filtration and concentrate the filtrate in vacuo to give N-[1(S)-ethoxycarbonyl-2-(4-aminophenyl)ethyl]-(S)-alanine, t-butyl ester.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:30][CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:29][CH:28]=[CH:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:37][CH:38]=2)[CH2:25][CH:26]=[CH:27][CH2:28][CH2:29]1
Reactant: Nc1ccc(CCN2CC=CCC2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CCN2CC=CCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
4-chlorobenzeneboronic acid (2.05 eq, 2.05 g), N-boc tyramine (1 eq, 6.55 mmol, 1.60 g), cooper(II)-acetate (1.01 eq, 1.20 g) and pyridine (5 eq, 2.64 ml) were dissolved in 70 ml of dry DCM. In the solution were added 4 Å molecular sieves (3 g) and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered over a celite pad, it was diluted with 150 ml of diethyl ether and was subsequently washed with 150 ml of 0.5 N HCl water solution, 150 ml of water and 150 ml of brine. The organic phase was dried, the solvent was evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 5-30% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was {2-[4-(4-chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.7 g, yield=68.14%, purity=94%). MS: [M−H]−=346.13 1H NMR (300 MHz; CDCl3) δ/ppm 1.42 (s, 9H), 2.75 (t, J=7.0 Hz, 2H), 3.35 (m, 2H), 6.87-6.95 (m, 4H), 7.14 (d, J=8.45 Hz, 2H), 7.22-7.28 (m, 2H)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10](#[N:12])[CH3:11]>>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)[CH2:11][C:10]#[N:12]
Reactant: O=Cc1cccc(I)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(I)c1

Procedure:
Acetonitrile addition to 3-iodobenzaldehyde (103) yielded 3-hydroxy-3-(3-iodophenyl)propanenitrile (104) as yellow oil. Yield (2.58 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 5.01 (m, 1H), 2.80 (d, J=6.4, 2H), 2.40 (bs, 1H).