Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([S:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: Sc1ccncc1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Sc2ccncc2)cc1)N1CCCC1CN1CCCC1

Procedure:
For example, (4-bromo-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (where Y═Br) is treated with a suitable nucleophile, in this case, 4-mercaptopyridine in a suitable solvent such as DMF with potassium carbonate and the reaction heated to reflux for 1-3 days to yield [4-(pyridin-4-ylsulfanyl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([NH2:15])=[O:14])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:12]([C:13]([NH2:15])=[O:14])[C:9](=[O:10])[CH2:8]2
Reactant: NC(=O)Nc1ccc(Cl)cc1CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Yield: 1.8 %

Procedure:
Cyclization of 4.78 g (0.021 mole) of 2-(5-chloro-2-ureidophenyl)acetic acid with 8.0 g (0.063 mole) of trifluoroacetic anhydride in 75 ml of trifluoroacetic acid, according to the method of Example 13, followed by recrystallization of the crude product from acetonitrile, gave 80 mg of the title compound, m.p. 211° C. (dec.).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13]C)=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCOc1ccc(F)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCOc1ccc(F)cc1C(=O)c1cnc(SC)nc1N

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-1-ethoxy-4-fluoro-benzene (prepared from 2-bromo-4-fluoro-phenol, Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1.[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCC1OCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-(4-chlorobutyl)-1,3-dioxolane and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 375.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N

Procedure:
1-[3-(Methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)piperazine (1.09 g, 3.46 mmol) was suspended in 5 mL THF and 10 mL MeOH in a 100 mL round bottom flask. NiCl2-6H2O (0.247 g, 1.04 mmol) was added, followed by slow addition of NaBH4 (0.392 g, 10.38 mmol). The reaction mixture was adsorbed on SiO2 and purified via column chromatography to afford 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline. (0.925 g, 3.24 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.91 (s, 3 H) 2.99-3.07 (m, 4 H) 3.19-3.27 (m, 4 H) 3.75 (s, 3 H) 4.28 (s, 2 H) 6.33 (dd, J=8.39, 2.43 Hz, 1 H) 6.49-6.58 (m, 2 H). ESIMS M+H)+=285.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])([CH3:6])[CH2:3][S:4][CH3:5].[I:19]N1C(=O)CCC1=O>>[CH3:6][C:2]([NH:7][C:8](=[O:18])[C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=[CH:13][C:14]=1[I:19])([CH3:1])[CH2:3][S:4][CH3:5]
Reactant: CSCC(C)(C)NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1I
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1[N+](=O)[O-]
Yield: 43 %

Procedure:
N-(1,1-Dimethyl-2-methylthioethyl)-2-nitrobenzamide was treated in the same manner as in Example 19, except that N-iodosuccinimide was used as the iodinating agent, to obtain N-(1,1-dimethyl-2-methylthioethyl)-2-iodo-6-nitrobenzamide (yield 43%, melting point 114–115° C.). Regioselectivity of iodination into the 2-position was 100%.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].O1CCCC1.Br[CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:24]([CH:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH3:25]
Reactant: CC(=O)C1=CNCCC1
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)CN1C=C(C(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was added under nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) and dry tetrahydrofuran (50 ml) stirring at room temperature. After one hour, 1-bromo-2-ethyl hexane (33.8 g, 0.175 mole) was added dropwise over 15 minutes and the mixture stirred overnight at room temperature. The reaction mixture was cautiously added to iced water (100 g) under nitrogen and extracted with diethyl ether (3×100 ml). The combined organic phase was dried over magnesium sulphate, concentrated under reduced pressure and the residue distilled to give methyl 1-(2-ethylhexyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (5) as a pale yellow oil (b.pt 140°-142° C./0.1 mm Hg).
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([C:14]1[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=1)=[C:7]2[C:11]([OH:13])=[O:12].O.C(=O)(O)[O-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[C:14]1[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=1)[CH:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: O=C(Cl)Cc1cccs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-2-carboxy-8-oxo-3-(2-phenylthiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) in a mixture of distilled water (35 cc) and acetone (24 cc) containing sodium bicarbonate (2 g) is cooled to -10° C. and then treated with a solution of (thien-2-yl)-acetyl chloride (0.86 cc) in acetone (10 cc), which is added dropwise in 8 minutes. The reaction mixture is stirred for 30 minutes at -10° C. and then for 3 hours at 20° C. The acetone is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. and ethyl acetate (150 cc) and a saturated sodium bicarbonate solution (100 cc) are added. The aqueous layer is extracted with ethyl acetate (100 cc), then treated with decolorising charcoal (1 g) and a filtration aid (diatomaceous earth powder) (5 g), and filtered on the filtration aid, rinsing with distilled water (2×50 cc). The combined filtrates are acidified to pH 2 with 4N hydrochloric acid. The precipitate is filtered off, washed with ethyl acetate (50 cc) and then triturated with isopropyl ether (100 cc) and dried. 2-Carboxy-8-oxo-3-(2-phenyl-thiazol-5-yl)-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.8 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([O:12][C:11]([F:10])([F:20])[F:21])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: Fc1cnc(Cl)nc1Nc1cccc(OC(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.12 (d, 1H, J=3 Hz), 7.68 (bs, 1H), 7.53 (dd, 1H, J=1.2 and 8.4 Hz), 7.41 9t, 1H, J=8.1 Hz), 7.04 (bdt, 2H); 19F NMR (CDCl3): −16430 and −44463; LCMS: purity: 89%; MS (m/e): 308 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:24][O:23][C:21]([C:20]1[CH2:19][N:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=1)[C:11]2=3)=[O:22]
Reactant: COC(=O)CCBr
Reactant: O=Cc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cccc3ccn(c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 7-formylindole (30 g, 0.206 mol) in dimethylformamide (930 mL) was added cesium carbonate (148.2 g, 0.454 mol) and the mixture was stirred vigorously at room temperature for 30 min. Methyl 3-bromopropionate (51.6 g, 0.308 mol) was added and the reaction mixture was heated to 80° C. for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water and saturated aqueous sodium chloride, and the aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was passed through a short silica plug and concentrated under reduced pressure. Recrystallization of the crude product from chloroform and hexanes gave 4H-pyrrolo[3,2, 1-ij]quinoline-5-carboxylic acid methyl ester (17 g, 38.7% yield). Chromatography of the mother liquor gave additional 4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (1.27 g, 2.9% yield) and 6H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (0.51 g, 1.2% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Clc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cnc(Cl)c2)nc1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A vial was charged with 4-chloro-1H-imidazole (450 mg, 4.4 mmol), 2-chloro-5-nitropyridine (1.04 g, 6.58 mmol), potassium carbonate (1.21 g, 8.78 mmol), and acetonitrile (10 mL). The vial was capped and heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-(4-chloro-1H-imidazol-1-yl)-5-nitropyridine (675 mg, 68%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 9.35 (d, J=2.4 Hz, 1H), 8.78 (dd, J=9.0, 2.6 Hz, 1H), 8.64 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]#[N:6].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:5][NH2:6]
Reactant: COCCOCOc1ccc(C#N)cc1Br
Agent: Cl
Solvent: C1CCOC1
Product: COCCOCOc1ccc(CN)cc1Br
Temperature: 0 °C
Yield: 55.1 %

Procedure:
Borane-tetrahydrofuran complex (280 mL, 1 M, 280 mmol) was added to a magnetically stirred solution of 3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile (10 g, 35 mmol) in tetrahydrofuran (20 mL) and the reaction mixture was refluxed for 30 minutes. The mixture was cooled to 0° C. and 1 N HCl was added very slowly until the pH was acidic. The tetrahydrofuran was removed by evaporation and the residual aqueous layer was washed with ethyl ether. The aqueous extract was basified with 2 N sodium hydroxide until alkaline pH and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated by evaporation to give 3-bromo-4-(2-methoxy-ethoxymethoxy)benzylamine (5.6 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11]Cl.[OH-].[Na+]>C(#N)C>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: ClCc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: NCCNCc1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Ethylenediamine (30 g) was dissolved in acetonitrile (200 ml), and pyrazinylmethyl chloride (12.9 g) was added dropwise to this solution at 5 to 10° C. After addition, the mixture was stirred at room temperature for 1 hour. Then, a 50% aqueous solution of sodium hydroxide (8 g) was added, and thereafter, volatile materials were removed at a bath temperature of 60° C. under 5 mmHg. The inorganic salt was then removed by filtration. Thus, N-(pyrazinylmethyl) ethylenediamine (14.1 g) was obtained as a colorless oil. nD20 =1.5359.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[C:22]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)CCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(OCCCCC(=O)OC)c2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 83 %

Procedure:
Using the procedure of example 11 and starting with 0.412 g (2.0 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 1.0 g (2.1 mmol) of 6-[6-[(methylsulfonyl)oxy]hexyl]-2-(5-methoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester, 6-(5-methoxy-5-oxopentyloxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid methyl ester was obtained in 83% yield (0.97 g) as a colorless oil. This diester (1.7 mmol) was saponified with 5 mL of 3N aqueous lithium hydroxide in 40 mL of tetrahydrofuran, at room temperature, for 20 hr. Work-up as in example 4 gave an oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.76 g (81%) of pure 2-(4-carboxybutoxy)-6-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7 -yl)oxy]hexyl]benzenepropanoic acid. Recrystallization from hexane-ethyl acetate (2:1) gave 0.64 g (68%) of a colorless solid, mp 103°-104° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]CC4C=CC=CC=4)=[CH:17][C:16]=3[O:29]CC3C=CC=CC=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[Pd]>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[OH:29])[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NC1CCCCC1)N1CCC(c2ccc(O)cc2O)C1
Reaction time: 18 h

Procedure:
In a 25 ml round-bottomed flask, 0.23 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid cyclohexylamide is dissolved in 4 ml of methanol in the presence of 3 ml of ethyl acetate and of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (7/3 heptane/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 90 °C
Yield: 39.2 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine (81 mg, 0.32 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (83 mg, 0.35 mmol) and DIPEA (162 μL, 0.95 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which and with MeOH followed by 2M NH3/MeOH (purification by SCX cartridge repeated three times). The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then triturated with MeOH to afford 176 as an off-white solid (47 mg, 40%). LCMS (Method K): RT 2.75 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 8.79 (1H, d, J=2.46 Hz), 8.61 (1H, s), 8.15-7.91 (4H, m), 7.71 (1H, dd, J=8.80, 4.84 Hz), 7.55-7.46 (1H, m), 7.11 (1H, td, J=9.33, 2.43 Hz), 6.93 (1H, dd, J=8.91, 2.44 Hz), 5.49 (1H, s), 1.62 (3H, d, J=6.83 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CO>[CH:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCC=COc1ccc(C=O)cc1
Yield: 92.5 %

Procedure:
To a 500 ml egg-plant type flask, 4-hydroxybenzaldehyde (12.2 g, 100 mmol), a 28% solution of sodium methylate in methanol (18.5 ml, 130 mmol of sodium methylate), methanol (60 ml) and 6-bromo-1-hexene (20.0 ml, 150 mmol) were charged and heated under reflux for 18 hours. The reaction mixture was concentrated to about a half volume by evaporation of volatile components. Then, toluene (200 ml) and water (100 ml) were added to the concentrated mixture and shaken, followed by removal of an aqueous phase. An organic phase was washed with water (150 ml×3) and dried over anhydrous magnesium sulfate (10 g). After removing solids by filtration, volatile components were evaporated off from a filtrate to obtain 4-(1-hexenyloxy)benzaldehyde (18.9 g).
Reaction SMILES: B.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][NH:19][C:20](=O)[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[OH:22])[CH:13]=[CH:14][C:15]=1[OH:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)CC>O1CCCC1>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH2:18][CH2:17][C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)=[CH:28][CH:27]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NCCc1ccc(O)c(OCc2ccccc2)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CCC(=O)O
Product: Oc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)cc2)cc1OCc1ccccc1

Procedure:
148 ml of 1.67M boron hydride in tetrahydrofurane were added to a solution of 11.3 g of N-[2-(3-benzyloxy-4-hydroxyphenyl)-ethyl]-4-benzyloxy-mandelamide (obtained as described in example 67) in 100 ml of tetrahydrofurane. After 3 hours under reflux, the mixture was cooled and 6.93 g of propionic acid were added. The mixture was refluxed again for 1 hour and then evaporated to dryness. The resulting oil was dissolved in methylene chloride, washed with water and diluted sodium hydroxide, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel column using methylene chloride/methanol/ammonium hydroxide=97/3/0.3 as eluent. N-[2-(4-Benzyloxyphenyl)-2-hydroxyethyl]-3-O-benzyldopamine was thus obtained, m.p. 124°-125° C. (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1nc(N)cc(Cl)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(NC(=O)OC(C)(C)C)n1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 6-chloro-2-methylpyrimidin-4-amine (1.0 equiv.) in THF (0.17M) was added BOC2O (1.1 equiv.) and DMAP (cat.). The reaction was allowed to stir overnight, then concentrated to a yellow crude, and filtered through a pad of SiO2 eluting with EtOAc and hexanes (1:1) to afford an off-white solid (78%). LCMS (m/z): 244.1 (MH+); LC Rt=3.69 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C(O)(=O)C.[CH3:23][NH2:24].[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:24][CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g) and molecular sieves in methanol (20 mL) at room temperature was added acetic acid (0.1 mL) and a solution of methylamine (219 mg) in methanol (1 ml). The reaction mixture was stirred at room temperature for 24 h. Then sodium borohydride (542 mg) was added portionwise and the reaction stirred at room temperature for a further 30 min. The reaction was then quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted into dichloromethane (2×10 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine as a white solid (0.95 g).