Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH2:7][N:8]1[CH2:28][CH2:27][C:11]2([O:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)=[O:18])[CH2:12]2)[CH2:10][CH2:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH:24]([C:21]1[S:22][CH:23]=[C:19]([C:17]([N:13]2[CH2:12][C:11]3([CH2:27][CH2:28][N:8]([CH2:7][C:6]4[CH:29]=[CH:30][C:31]([C:32]([F:35])([F:33])[F:34])=[C:4]([CH2:3][CH:2]=[O:1])[CH:5]=4)[CH2:9][CH2:10]3)[O:16][CH2:15][CH2:14]2)=[O:18])[N:20]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(C(F)(F)F)c(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(C(F)(F)F)c(CC=O)c4)CC3)C2)cs1
Reaction time: 1.5 h

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 16 step c) using (9-(3-(2-hydroxyethyl)-4-(trifluoromethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (0.32 g) (Example 270, step b). The mixture was stirred for 90 min after the addition of the Dess-Martin periodinane. Yield 0.38 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1Cl.CC(C)([O-])C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C(OCC)(=O)C.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].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:21]4[CH:20]=[N:19][CH:18]=[CH:17][C:22]=4[O:15][C:9]=3[C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: Clc1ccncc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1oc3ccncc3c1C2
Temperature: 100 °C
Yield: 3.9 %

Procedure:
To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.5 g), 3-bromo-4-chloro-pyridine (2 g), sodium t-butoxide (3 g), Pd2dba3 (476 mg), and S-Phos (512 mg), toluene (20 ml) was added, and the mixture was stirred and heated at 100° C. overnight under nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine. Thereafter, the organic layer was dried over sodium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (112 mg, 4%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[C:20](=[O:25])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)[CH2:18]2.[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][OH:45])=[CH:42][CH:41]=1>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>[Cl:24][C:22]1[CH:23]=[C:15]([O:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)[CH:16]=[C:17]2[C:21]=1[C:20](=[O:25])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)[CH2:18]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(CO)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)cc1
Temperature: 95 °C
Yield: 36.8 %

Procedure:
Palladium acetate (0.54 mg, 0.0024 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (1.2 mg, 0.003 mmol), and cesium carbonate (58.6 mg, 0.18 mmol) were added to a vial and the vial was filled with Argon. Toluene (1.5 mL) was added and the vial was degassed with a pump and filled again with Argon. 5-Bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.12 mmol) and 4-methoxy-benzyl alcohol (33.2 mg, 0.24 mmol) were added and the mixture was stirred at 95° C. for forty-five hours. The cooled mixture was then diluted with diethyl ether and filtered through Celite®. Column chromatography (20% EtOAc/Hexanes to 100% EtOAc) provided the title compound (21.1 mg, 37%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12]>C(O)=O>[CH:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:3]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNC(CC(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Formic acid (1.0 ml, 26.6 mmol) was added dropwise to 2.0 ml (21.4 mmol) of acetic anhydride in an ice bath. After that, the ice bath was removed, and the solution was stirred at 50° C. for 15 minutes. After allowing to stand for 15 minutes, the resulting solution was cooled again with an ice bath and was added dropwise to a solution of 586 mg (3.55 mmol) of (±)-3-amino-3-phenylpropanoic acid in 0.5 ml of formic acid previously cooled to a temperature not higher than 10° C. The mixture was stirred for 40 minutes as it was, and, when the solution became room temperature, it was stirred for 80 minutes more. The residue prepared by concentrating the reaction solution in vacuo was recrystallized from water to give 624 mg (3.23 mmol) of (±)-3-formylamino-3-phenylpropanoic acid in a yield of 91.0% (melting point: 127 to 128° C.).
Reaction SMILES: C1(N)CCCC1.BrC1C(Cl)=NC(Cl)=NC=1.[Br:16][C:17]1[C:18]([NH:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[N:19][C:20]([Cl:23])=[N:21][CH:22]=1>>[Br:16][C:17]1[C:18]([NH:24][CH:25]2[CH2:28][CH2:29][CH2:27][CH2:26]2)=[N:19][C:20]([Cl:23])=[N:21][CH:22]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: Clc1ncc(Br)c(Cl)n1
Agent: NC1CCCC1
Product: Clc1ncc(Br)c(NC2CCCC2)n1

Procedure:
(5-Bromo-2-chloro-pyrimidin-4-yl)cyclopentylamine is prepared from cyclopentyl amine and 5-bromo-2,4-dichloropyrimidine using a method similar to that for the preparation of (5-Bromo-2-chloro-pyrimidin-4-yl)-(1-ethylpropyl)amine given in Example 137.
Reaction SMILES: O[NH:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[OH:12].CN(C)C=O.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3]([OH:13])=[N:2][O:12][C:5]=2[CH:6]=1
Reactant: O=C(NO)c1ccc(CO)cc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Oc1noc2cc(CCl)ccc12
Reaction time: 2 h

Procedure:
In 50 mL of methylene chloride was suspended 10.0 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide. To this, 0.21 mL of N,N-dimethylformamide was added. This was cooled and 8.36 mL of thionyl chloride was added dropwise under ice-cooling. After 2 hours of stirring under heating reflux, 13 mL of solvent was distilled off under atmospheric pressure. To the reaction mixture was added 13 mL of methylene chloride, 4.64 mL of pyridine was added dropwise at 20-30° C., and the results were stirred for 1 hour at the same temperature. After adding 20 mL of water and 50 mL of acetone, 50 mL of solvent was distilled off under atmospheric pressure, solids were filtered, and 6.45 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol in the form of a pale yellowish-white solid was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25]C(C)(C)[N:23]([C:28](=[O:32])[CH:29]([F:31])[F:30])[C@@H:22]3[CH2:33][F:34])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([OH:25])[C@H:22]([NH:23][C:28](=[O:32])[CH:29]([F:30])[F:31])[CH2:33][F:34])=[CH:17][CH:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (5-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyrimidin-2-ylmethyl)-carbamic acid tert-butyl ester (0.125 g, 0.253 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL) at room temperature. Resulting reaction mixture is allowed to stir at room temperature for 5 hours. The solvent evaporated in vacuo and the crude material is striped out with CH2Cl2 followed by washing with diethyl ether and dried in lipholiser to afford title compound (0.1 g): 1H NMR (400 MHz, DMSO-d6) δ: 4.31-4.33 (m, 1.5H), 4.36 (d, J=8.84 Hz, 2H), 4.42-4.46 (m, 0.5H), 4.56-4.57 (m, 0.5H), 4.66-4.70 (m, 0.5H), 4.92 (t, J=3.76 Hz, 1H), 5.98 (d, J=4.6 Hz, 1H), 6.20 (t, J=53.72 Hz, 1H), 7.52 (d, J=8.24 Hz, 2H), 7.84 (d, J=8.24 Hz, 2H), 8.36 (bs, 2H), 7.86 (d, J=8.84 Hz, 1H), 9.24 (s, 2H). LC-MS (m/z): [M+H]=354.9.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.Cl>CC(N(C)C)=O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCCc1ccccc1

Procedure:
A solution of 15.3 g of 2-chloro-5-nitrobenzoic acid and 49 g of 3-phenylpropylamine in 60 ml of dimethylacetamide is heated at 145° C. for 2 hours. After cooling, 300 ml of water are added, and the mixture is acidified (pH 2 to 1) with 2 N HCl.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[N+:22]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(#N)C>[N+:22]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32][N:2]([CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:1])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CNCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1ccc2ccccc2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a stirred suspension of 2-(methylaminomethyl)quinoline, prepared by the procedure of Example 3, Step 1, (3.67 g, 21.35 mmol), sodium iodide (2.78 g, 18.56 mmol), and potassium carbonate (3.08 g, 138.21 mmol) in acetonitrile (80 mL) was added 1-(4-nitrophenoxy)-3-chloropropane (4.00 g, 18.56 mmol). The mixture was stirred at 80° C. overnight, concentrated and partitioned between 10% K2CO3 and ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated to afford an oil. The product was purified by HPLC (10% methanol/dichloromethane) to afford 2.34 g (36%) of pure product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][N:4]=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[F:13][C:2]([F:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][NH2:4]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(F)(F)c1ccccn1

Procedure:
A stirred solution of 100 mg of 2,2-difluoro-2-(2-pyridyl)ethyl azide was hydrogenated in 10 ml of ethyl acetate over 100 mg of 10% palladium on carbon under a balloon of hydrogen for 1 h. The catalyst was removed by filtration and the solvents removed at reduced pressure to give 1-10 as a yellow oil: 1H NMR (CDCl3) δ6 8.66 (d, 1H, 4.2 Hz), 7.82 (td,1H, 7.7, 1.7 Hz), 7.68 (d, 1H, 8.1 Hz), 7.37-7.40 (m, 1H), 3.44 (t, 2 H, 14.3 Hz), 1.41 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1)(=O)=O.CN(C=O)C>C1COCC1>[N:34]1([C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1
Reactant: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CS(=O)(=O)n1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)n3nnc4ccccc43)cc2)c1
Yield: 91.8 %

Procedure:
6′-Methyl-3′-[(propylamino)carbonyl]-1,1′-biphenyl-4-carboxylic acid (121 mg, 0.41 mmol), triethylamine (100 μl) and 1-(methylsulphonyl)-1H-benzotriazole (119 mg, 0.6 mmol) were mixed in THF (3 ml) and DMF (0.5 ml) and heated at reflux for 3 h. The reaction was concentrated under vacuum and partitioned between chloroform (5 ml) and water (5 ml). The aqueous was washed with chloroform (3 ml) and the combined organics reduced to dryness under vacuum. The residue was chromatographed on an SPE (silica, 5 g) eluting with chloroform, ether and ethylacetate, which after evaporation of the solvent under vacuum gave 4′-[(1H-1,2,3benzotriazol-1-yl)carbonyl]-6-methyl-N-propyl-1,1′-biphenyl-3-carboxamide (150 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH:19]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[OH:36][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
To a solution of diisopropylamine (1.203 mL, 8.44 mmol) in THF (10 mL) was added n-BuLi/hexane (3.38 mL, 8.44 mmol) dropwise at −78° C. The reaction mixture was stirred in the bath for 5 min and then stirred in ice bath for 30 min. The reaction mixture was added dropwise a solution of tert-butyl cyclopropanecarboxylate (1 g, 7.03 mmol) in THF (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 h. The solution of benzaldehyde (0.746 g, 7.03 mmol) in THF (2 mL) was added dropwise at −78° C. Then the solution was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with NH4Cl, then diluted with EtOAc. Then organic phase was washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, and concentrated to yield an oil. The crude was purified by silica chromatography with 0-50% EtOAc/Hex to yield tert-butyl 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylate (1.01 g, 57.8% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.48-7.40 (m, 2H), 7.38-7.23 (m, 3H), 4.70 (d, J=7.5 Hz, 1H), 3.55 (d, J=7.8 Hz, 1H), 1.43-1.33 (m, 10H), 1.17 (ddd, J=9.6, 6.6, 3.9 Hz, 1H), 0.99-0.79 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[C:22]([Cl:24])[C:21]([F:25])=[C:20](Cl)[N:19]=1>C1COCC1.O>[Cl:17][C:18]1[N:19]=[C:20]([N:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[C:21]([F:25])=[C:22]([Cl:24])[N:23]=1
Reactant: CNCc1ccncc1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccncc1)c1nc(Cl)nc(Cl)c1F
Reaction time: 2.5 h
Yield: 49 %

Procedure:
Commercially available N-methyl-1-(4-pyridinyl)methanamine (0.305 g, 2.5 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.38 mL, 2.73 mmol), followed by 2,4,6-trichloro-5-fluoropyrimidine (0.5 g, 2.5 mmol), which was dissolved in THF (5 mL). The reaction was left to stir for 2.5 hours. The reaction mixture was diluted with water, then extracted with ether. The organics were dried (MgSO4) and concentrated. The resulting material was purified via filtration over silica gel with a solvent mixture of 5% MeOH in 95% DCM as the mobile phase to provide 2,6-dichloro-5-fluoro-N-methyl-N-(4-pyridinylmethyl)-4-pyrimidinamine as a brown oily solid (0.3516 g, 49%). LCMS: (M+H)+=287.0.
Reaction SMILES: O[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O.CN(C)C1C=CC=CC=1>>[Cl:19][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(O)cc(=O)n2c1CCCC2
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1c(Cl)cc(=O)n2c1CCCC2

Procedure:
Methyl 8-hydroxy-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7a, 2 g, 9.52 mmol, 1 eq) was suspended in phosphorous oxychloride (5.3 ml, 57 mmol, 6 eq) and dimethylaniline (242 μl, 1.9 mmol, 0.2 eq) under nitrogen and stirred at RT for 16 h. The solution was concentrated in vacuo, quenched with ice and made basic with sat. NaHCO3 solution. The aqueous solution was concentrated in vacuo and the residue triturated in 20% MeOH/DCM. Inorganic salts were removed by filtration and the filtrate evaporated to dryness. The resulting solid was purified by flash chromatography using 75% EtOAc/DCM as eluent to give the title compound as a white solid. (1.43 g, 63%) [M+H] calc'd for C11H12ClNO3, 242. found, 242
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7](=[CH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:21]1)[CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:34])[CH:7]([CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:21]1)[CH2:8][C:9]([OH:11])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(CC(=O)O)C(=O)OC(C)(C)C)CC1

Procedure:
A solution of trans-2-(4-tert-Butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (243 mg, 0.51 mmol) and palladium (5% on charcoal) in ethanol (15 mL) was hydrogenated at 4 bar for 3 h. The catalyst was removed from the reaction mixture by filtration. The catalyst was washed with ethanol and the solution was concentrated under reduced pressure to give crude trans-2-(4-tert-Butoxycarbonylamino-cyclohexylmethyl)-succinic acid 1-tert-butyl ester (217 mg, >100%).
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([NH2:26])=[C:24]([C:27]#[C:28][Si](C)(C)C)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CN1C(=O)CCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]3[NH:26][CH:28]=[CH:27][C:24]=3[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(C#C[Si](C)(C)C)c2N)CC1
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution of tBuOK (0.063 g, 0.56 mmol) in NMP (4 mL) was added 4-(5-Amino-6-trimethylsilanylethynyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.27 mmol) in NMP (1 mL) under N2. The mixture was vigorously stirred at room temperature for 4 hours. The reaction was quenched with water (1 mL) and ethyl acetate (50 mL). The organic phase was washed brine and water until NMP was gone, then dried over MgSO4, filtered and concentrated. The residue was subject to chromatography on silica gel to afford the product 4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 mg, 53%). 1H NMR (CDCl3, 400 Hz) δ 9.47 (s, 1H), 8.49 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 3.85-3.82 (m, 4H), 3.61-3.58 (m, 4H). 1.49 (s, 9H). MS (ESI+) [M+H]+ 304.
Reaction SMILES: [Na].Cl.[CH3:3][C@@H:4]([CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[NH:16])=[CH:13][CH:12]=1.[CH2:22]([CH:30]([C:36](OCC)=[O:37])[C:31](OCC)=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C[O-].[Na+].S(=O)(=O)(O)O>CO>[CH2:22]([C:30]1[C:31]([OH:32])=[N:16][C:15]([C:14]2[CH:18]=[CH:19][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:3])[CH2:20][CH3:21])=[CH:12][CH:13]=2)=[N:17][C:36]=1[OH:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: CC[C@H](C)CCCCCOc1ccc(C(=N)N)cc1
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCCCCCc1c(O)nc(-c2ccc(OCCCCC[C@@H](C)CC)cc2)nc1O

Procedure:
Pour 1.15 g sodium metal, and 33 ml dry methanol into 100 ml four-mouth flask; add 5 g of optically active (s)-4-(6-methyloctyloxy)benzamidine hydrochloric acid salt, then pour 4.55 g of diethyl n-octylmalonate into this sodium methylate solution and then allow to react for 18 hours under heat and reflux conditions. After cooling, acidify the mixture utilizing concentrated sulfuric acid, and extract the crystals. The impure crystals are purified, and then optically active 6.32 g of (s)-5-n-octyl-2-[4-(6methyloctyloxy)phenyl]-4,6-dihydroxy-pyrimidine is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Br[CH2:10][CH2:11][O:12][CH3:13].O>CN(C=O)C>[CH3:13][O:12][CH2:11][CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH3:3]
Reactant: COCCBr
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1ccnc1C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
NaH (60%, 620 mg) was added to a solution of 2-methyl-1H-imidazole (1.06 g, 12.95 mmol) in DMF (8 mL). After stirring for 15 minutes, 1-bromo-2-methoxyethane (2.16 g, 15.54 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80° C. under microwave irradiation for 60 minutes. Water (1 mL) was added and all solvents were removed by high vacuum. EtOAc was added to the residue, stirred for 15 minutes, filtered and concentrated in vacuo to afford the title compound as a colourless oil (604 mg, 33%) that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:16])[NH:12][CH2:13][CH:14]=O)[CH2:7][CH2:6]1)=[O:4].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[O:16][CH:14]=[CH:13][N:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCC=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2ncco2)CC1
Temperature: 100 °C

Procedure:
A mixture of trans-4-(2-oxo-ethylcarbamoyl)-cyclohexanecarboxylic acid methyl ester (830 mg, 3.65 mmol) and phosphorus oxychloride (2.80 g, 18.3 mmol) was heated at 100° C. for 20 h. After cooling to room temperature the reaction mixture was poured on crushed ice and basified to pH 7-8 by addition of 1 M aqueous sodium hydroxide solution. The mixture was extracted with three 100 ml-portions of ethyl acetate. The combined organic layers were washed with one 50 ml-portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (175 mg, 23%) as white solid, with a purity of 90% according to GC. MS m/e: 210 ([M+H]+)