Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].O>C(OCC)C>[CH2:9]([C:4]1[CH:3]=[C:2]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: CCc1cc(Br)cc(C)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nc(CC)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 19.4 g of 4-bromo-2-ethyl-6-methylpyridine from (a) above in 275 ml of diethyl ether chilled to -70° C. under argon was added dropwise over 1/2 hour 38.8 ml of n-butyllithium while maintaining the reaction temperature below -65° C. Stirring was continued at -70° C. for 1 hour and then 22 ml (26.4 g) of tributyltin chloride in 25 ml of diethyl ether were added over 20 minutes. The mixture was allowed to warm to 20° C. and 200 ml of water was added. The ether layer was separated, dried over magnesium sulfate and concentrated in vacuo (90° C.; 50 mm). Hexane was added and the mixture was filtered and the filtrate was concentrated in vacuo (15 mm) to give the title product as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:14])=[C:5]([Cl:13])[C:6]=1[C@@H:7]1[CH2:9][C@H:8]1[C:10](=O)[CH3:11].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO.O>[CH3:22][O:23][N:24]=[C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[S:3][C:2]=1[Cl:1])[CH3:11]
Reactant: CON
Reactant: CC(=O)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CON=C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a stirred solution of trans 1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethanone (2.7 g; 10 mmol) prepared as described in example P29, in methanol (20 ml) at ambient temperature was added pyridine (1.25 ml; 15 mmol) and methoxyamine hydrochloride (1.3 g; 15 mmol). The reaction mixture was stirred for 4 hours at ambient temperature then poured in water (50 ml) and extracted with dichloromethane (3×30 ml). Combined organic layers were washed with water (30 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 2.85 g (95% of theory) of trans 1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethanone O-methyl-oxime as an E/Z mixture in form of an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH2:22][Cl:23])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Temperature: 70 °C
Yield: 97.7 %

Procedure:
To a solution of 4-hydroxy-3-methoxy-benzoic acid methyl ester (10 g, 54.8 mmol) and potassium carbonate (22.75 g, 164.4 mmol) in DMF (100 mL) was added 1-bromo-2-chloro-ethane (22.7 mL, 274 mmol). The mixture was heated at 70° C. for 3 h and monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine. The organic layer was dried (Na2SO4) and concentrated to afford 4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester (13.1 gm, 97%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 6.90 (d, 1H), 4.35 (t, 2H), 3.90 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:16]1([N:19]([CH3:27])[C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][N:21]=2)[CH2:18][CH2:17]1>>[CH:16]1([N:19]([CH3:27])[C:20]2[N:21]=[CH:22][C:23]([NH:26][C:13]([C:3]3[C:2]([CH3:1])=[N:6][N:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:4]=3)=[O:15])=[CH:24][CH:25]=2)[CH2:18][CH2:17]1
Reactant: CN(c1ccc(N)cn1)C1CC1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)C2CC2)nc1

Procedure:
With a procedure similar to example 16 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N2-cyclopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H20N6O (m/e) 348, obsd 349 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][C@@H:35]1[CH2:39][NH:38][C@H:37]([CH2:40][O:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=2)[CH2:36]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:38]2[CH2:39][C@@H:35]([O:34][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)[CH2:36][C@H:37]2[CH2:40][O:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (310 mg, 0.93 mmol), methyl 4-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (350 mg, 0.93 mmol), EDC.HCl (267 mg, 1.40 mmol) and DMAP (171 mg, 1.40 mmol) in DMF (10 ml) was stirred at room temperature for 3 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(1/1)CHCl3/MeOH(50/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (450 mg, 68%) as a pale brown amorphous. 1H-NMR (CDCl3) δ2.32 (m, 1H), 2.58 (d, J=14.5 Hz, 1H), 3.63 (d, J=2.7 Hz, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 3.84-3.95 (m, 2H), 4.15-4.64 (m, 4H), 5.11 (br, 1H), 6.79-7.06 (m, 7H), 7.21-7.46 (m, 7H), 7.66-7.77 (m, 3H), 7.92 (d, J=8.8 Hz, 1H), 7.97 (m, 1H), 8.17 (d, J=8.4 Hz, 1H); MS (ESI) m/z 694 (M++1), 696 (M++3).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].O>CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[CH2:16][CH2:15]3)[OH:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CCN2CCC(C(=O)c3ccc(-n4ccnc4)cc3)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CCN2CCC(C(O)c3ccc(-n4ccnc4)cc3)CC2)cc1OC
Yield: 48.8 %

Procedure:
To a stirred solution of [4-(1H-imidazol-1-yl)phenyl][1-[2-(3,4-dimethoxyphenyl)ethyl]-4-piperidinyl]methanone (5.90 g, 14.1 mmol) in methanol (100 ml) at 0° C. was added sodium borohydride (1.80 g, 47.6 g mmol) in three equal portions over a 24 hour period. Water was added and the solution was concentrated to a white suspension. This aqueous suspension was extracted twice with dichloromethane. The combined organic layers were dried (MgSO4), and filtered through a pad of silica gel (eluting with acetone). The eluent was concentrated and the resulting solid was recrystallized from tetrahydrofuran to afford α-[4-(1H-imidazol-1-yl)phenyl]-1-[2-(3,4-dimethoxyphenyl)ethyl]-4-piperidine methanol (2.9 g, 49%): m.p. 59°-60° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[S:16])[O:15][CH2:14][CH2:13][CH2:12]1.O>O1CCCC1>[SH:16][CH2:11][CH2:12][CH2:13][C:14]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: S=C1CCCO1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCS)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
Sodium hydride (60% in oil dispersion, 1.22 g, 50.9 mmol) was washed with dry tetrahydrofuran (20 ml×3) under nitrogen atomosphere. Freshly distilled tetrahydrofuran (50 ml) was added and the mixture was cooled to 0° C. with an ice bath. To this mixture was added portionwise solution of benzyl alcohol (5 g, 46.2 mmol) in dry tetrahydrofuran (10 ml) and the mixture was stirred for 1 hour at said temperature. To the resulting mixture was added γ-thiobutyrolactone (5.2 g, 50.9 mmol) slowly and the resulting mixture was warmed to room temperature. After stirring for 1 hour, H2O (30 ml) was added carefully and tetrahydrofuran was removed under reduced pressure. The residue was extracted three times with AcOEt. The organic layers were combined, washed with brine, and dried over magnesium sulfate. The solvent was evaporated to give 9.96 g of benzyl 4-mercaptobutyrate as a colorless oil which was taken to the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[S:8][S:7][CH2:6]1>C(Cl)Cl>[S:7]1[CH2:6][CH2:5][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:3])=[O:16])[S:8]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: ClCCl
Product: O=C(Cl)CCCCC1CCSS1
Reaction time: 3 h

Procedure:
To a stirred solution of thionyl chloride (1.4 mL, 7.5 mmol) in CH2Cl2 (30 ml) at 0° C. was added a solution of lipoic acid (3.0 g, 5 mmol), dissolved in dichloromethane, dropwise over 1 h. The mixture was allowed to stir for additional 3 h. at the same temperature. After completion of the reaction the solvent was removed under vacuum using a dry-ice collection trap being very careful not to heat the reaction mixture since this will decompose the product. Reaction proceeds with quantitative yield.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](=[O:6])[CH3:5])#[N:2].[H][H]>CO.[Pd]>[OH2:6].[C:1]([CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:4](=[O:6])[CH3:5])#[N:2]
Reactant: [H][H]
Reactant: CC(=O)C(C#N)=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)C(C#N)Cc1ccccc1
Product: O

Procedure:
A sample of 3-cyano-4-phenyl-3-buten-2-one, prepared according to the procedure of Example 9 (5.0 g, 29.24 mmol), was dissolved in methanol (100 mL) containing 10% Pd—C (ca. 0.1 g, Aldrich) and hydrogenated at 50 psi hydrogen pressure for 2 h. The mixture was filtered through Celite to remove catalyst and an analytical sample prepared by concentrating a portion of the filtrate to give a pale-yellow oil. The oil was passed through a short pad of silica gel (hexane—ethyl acetate 7:3) and the desired fractions evaporated to give the title compound as a straw-colored oil. The remaining material was used directly in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:33]1([C:39]2[N:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41][CH:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N1CCOCC1)C>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:45]([C:42]3[CH:41]=[CH:40][C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:44][CH:43]=3)=[O:46])[CH2:14][C@@H:13]2[CH3:18])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccc(N3CCOCC3)nc2)CCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a suspension of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine hydrochloride (Description 4) (105 mg, 0.338 mmol), EDC (71.3 mg, 0.372 mmol), HOBT.H2O (56.9 mg, 0.372 mmol) and 6-(4-morpholinyl)-3-pyridinecarboxylic acid (77 mg, 0.372 mmol) in DCM (5 ml) was added N-ethyl morpholine (0.090 mL, 0.710 mmol). The reaction was stirred for 18 h at ambient temperature. To the reaction was added water (3 ml) and the organic layer collected via a hydrophobic frit. The organic layer was reduced in volume to approximately 2 ml then loaded onto a silica SP4 chromatography cartridge. The cartridge was eluted with a gradient from 60% ethyl acetate in iso-hexane to ethyl acetate then ethyl acetate. Fractions containing the desired product were combined and reduced in vacuo to yield the title compound as a white solid (88 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:19](=S)=[S:20]>C(O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][N:5]1[CH2:4][C:3]2[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:1][C:19]1=[S:20]
Reactant: S=C=S
Reactant: COc1ccccc1CNCc1ccccc1N
Solvent: CCO
Product: COc1ccccc1CN1Cc2ccccc2NC1=S

Procedure:
4.0 g (16.51 mmol) (2-aminobenzyl)(2-methoxybenzyl)amine in 100 mL ethanol was mixed with 40 mL CS2 and heated at reflux for 8 hours, forming a yellow precipitate. The mixture was evaluated and the resulting solids were recrystallized in ethanol; 4.24 g white solids.
Reaction SMILES: [CH2:1]([N:8](C(C(C)(C)C)=O)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH2:1]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(Cc1ccccc1)C(=O)C(C)(C)C)C2
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](NCc1ccccc1)C2
Reaction time: 7 h
Yield: 73 %

Procedure:
From N-benzyl-N-tert-butylcarbonyl-N-[(2S)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]amine: TFA (0.330 mL, 4.275 mmol) was added to a 0° C. cooled solution of starting material (0.381 g, 0.855 mmol) in CH2Cl2 (15 mL). The reaction was allowed to reach room temperature, and stirred at this temperature for 7 h. It was poured into H2O (20 mL), extracted with CH2Cl2 (1×25 mL) and washed with NaOH aqueous solution (10%, 2×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was flash chromatographed on silica gel (0-5-10% MeOH/CH2Cl2) to give 0.215 g of the title product (Rf=0.2 (10% MeOH/CH2Cl2), yellow oil, 73% yield).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.Cl[CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C[Si]([C:26]#[N:27])(C)C>C(Cl)Cl.O>[C:26]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)#[N:27]
Reactant: C[Si](C)(C)C#N
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: N#CC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 88.9 %

Procedure:
6.0 g (23.0 mmol) of tin tetrachloride are slowly added to a solution of 21.1 g (92.3 mmol) of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene [V. Mychajlyszyn et al, Coll. Czech. Chem. Comm. 24, 3955 (1959)] and 11.3 g (114 mmol) of trimethylsilylcyanide in 150 ml of methylene chloride. The reaction mixture is stirred at room temperature for 10 hours and then diluted with 150 ml of methylene chloride, and 200 ml of water are added. The organic phase is separated off, washed with dilute sodium bicarbonate solution, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from toluene gives 18.0 g (88.9%) of 5-cyano-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene, melting point 89°-90° C. (compound (104), Table 1).
Reaction SMILES: O.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].Cl.[CH2:16](O)[CH3:17]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:16][CH3:17]
Reactant: CCCCCCCCCCBr
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCBr
Temperature: 75 °C

Procedure:
The ground polymer of Example 23 (5 g) was placed in a 500 mL 3-necked round-bottomed flask and suspended in 100 mL deionized water and the suspension was stirred with a mechanical stirrer. To this swollen gel, a solution of 15 g 1-bromodecane in 100 mL ethanol was added and the reaction mixture was stirred for 10 minutes. 2 g 50% aqueous sodium hydroxide was then added and the reaction mixture was stirred at room temperature for 40 minutes followed by heating to 75° C. Subsequently, an additional 4 g 50% NaOH was added in a 1 g batch at an interval of 1.5 hr (the base addition maintained a pH between 10 to 12). The reaction mixture was allowed to stir at 75° C. for a total period of 20 hr. After cooling to 30° C., 2 mL concentrated HCl was added and the mixture was stirred for 30 minutes. The polymer was filtered off and washed with 500 mL deionized water and 500 mL methanol. The filtered polymer particles were slurried in methanol (400 mL), stirred for 40 minutes and reisolated by filtration. This process was then repeated. The polymer was suspended in 500 mL 2M NaCl solution and the suspension was stirred for 40 minutes. The polymer was filtered off and this NaCl treatment was repeated two more times. The fitered polymer cake was washed with 500 mL deionized water and suspended in 500 mL deionized water. After stirring the suspension for 30 minutes, the polymer was filtered off and resuspended in 500 mL deionized water. The resulting suspension was stirred for 30 minutes. 1 mL concentrated HCl was added to the suspension, which was then stirred for 35 minutes. The pH of the suspension was found to be 2.2. The polymer was then filtered off and dried at 60° C. in a forced air oven, yielding 13.3 g of the alkylated polymer as a pale white solid. The polymer was ground and passed through a 140 mesh sieve.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:23])[NH:9][C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:12][CH:13]=[N:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].IC.[C:26](=O)(O)[O-].[Na+]>O1CCCC1>[C:3]([O:7][C:8](=[O:23])[N:9]([CH3:26])[C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:12][CH:13]=[N:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1ccccc1-c1ncncc1NC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccccc1-c1ncncc1N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (75 mg, 1.87 mmol) was added to a stirring solution of (4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert-butyl ester (410 mmol, 1.44 mmol) in tetrahydrofuran (10 mL) under Argon atmosphere. After 10 min., iodomethane (117 μL, 1.87 mmol) was added. The reaction mixture was stirred for 16 hours and then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by removal of volatiles gave the crude product. Flash chromatography on silica gel (33% ethyl acetate in n-hexane) gave the product as a yellow solid (242 mg, 56%) which was pure enough for the next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[CH:14][N:15]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cn2)CC1

Procedure:
4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and 1-Boc-piperazine following a procedure similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 10-30% EtOAc in hexanes gradient. HRMS m/z calcd for C25H34N4O3 [M+H]+: 439.2704. Found: 439.2704.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.[OH:38][CH:39]([C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44])[CH3:40]>CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]=[C:13]([NH:44][C:43]4[CH:45]=[CH:46][CH:47]=[C:41]([CH:39]([OH:38])[CH3:40])[CH:42]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc(NC(=O)c3cccc(C(F)(F)F)c3)c2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: CC(O)c1cccc(N)c1
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(Nc2ncc3cc(-c4c(Cl)ccc(NC(=O)c5cccc(C(F)(F)F)c5)c4Cl)c(=O)n(C)c3n2)c1
Temperature: 120 °C

Procedure:
A mixture of N-[2,4-dichloro-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-phenyl]-3-trifluoromethyl-benzamide (20 mg, 0.035 mmol) and 3-(1-hydroxyethyl)-aniline (50 mg, 0.364 mmol) is heated at 120° C. for ten minutes. The mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by prep-HPLC to give N-(2,4-dichloro-3-{2-[3-(1-hydroxy-ethyl)-phenylamino]-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide as a white solid. (17.9 mg, 81.4%). 1H NMR (CD3OD): δ 10.50 (s, 1H), 8.57 (d, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.86 (d, 1H), 7.68 (t, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.52 (d, 1H), 7.41 (t, 1H), 7.21 (s, 1H), 7.20 (d, 1H), 4.98 (q, 1H), 3.83 (s, 3H), 1.54 (d, 2H); MS m/z 629.10 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:6].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Br-:6].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Yield: 84.6 %

Procedure:
A mixture of 3-fluorobenzyl bromide (5 g) and triphenyl phosphine (6.94 g) in toluene (50 mL) was heated at reflux for 3 hours. After cooling, the solid was collected by filtration, washed with toluene and dried under vacuum at 50° C. to give (3-fluorobenzyl)triphenylphosphonium bromide (10.1 g).