Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:6][CH:7]=1.[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:45]1([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:12][C@H:11]([S:13][C:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C@H:9]3[CH2:33][O:34][CH2:35][C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=3[F:44])=[N:6][CH:7]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(Br)cn2)cc1F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(-c3ccccc3)cn2)cc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
A solution of 1.35 g (2 mmol) (2S,4R)-5-Bromo-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 12 ml dimethoxyethane were added to a suspension of 0.116 g (0.1 mmol) tetrakis(triphenylphosphine)palladium in 1.4 ml dimethoxyethane and stirred for 15 min. 0.29 g (2.4 mmol) Phenylboronic acid in 3.4 ml EtOH was then added and after 10 min, 8.8 ml of a aqueous 2 M Na2CO3 solution. The reaction was heated for 2 h at 90° C., evaporated and extracted wit H2O/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (toluene) gave 0.48 g (36%) (2S,4R)-5-Phenyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 674 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH2:35][CH3:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:41]3[CH:42]=[CH:43][C:38]([C:34](=[O:37])[CH2:35][CH3:36])=[CH:39][CH:40]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CCC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: CCC(=O)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-propionyl-phenyl boronic acid (712 m g, 4.0 mmol) according to general procedure G to give {4-[4-(2,4-dichloro-phenyl)-2-(4′-propionyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:20].[OH:21]P([O-])([O-])=O.[K+].[K+].OP([O-])(O)=O.[K+]>CS(C)=O.O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:20])=[O:21]
Reactant: CCOC(=O)CCN1C(=O)c2ccc(CBr)cc2C1=O
Reactant: O=P([O-])([O-])O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCN1C(=O)c2ccc(C=O)cc2C1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The crude material from step 2 was dissolved in DMSO (70 mL). Powdered K2HPO4 (18 g, 0.10 mol) and KH2PO4 (7 g, 0.05 mol) were added. The mixture was stirred at 80° C. for 5 hours, diluted with water (500 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), and concentrated. After column chromatography (hexane, ethyl acetate 3:1) 4.8 g of the title compound was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=O)[O:22]C(C)(C)C)[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.[C:28](O)([C:30](F)(F)F)=O.C(Cl)(=O)C=C>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:22])[CH:28]=[CH2:30])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(SC)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (51) (651 mg, 1.69 mmol) in 10 mL of DCM at RT was added 3 mL of TFA. The resulting homogeneous solution was stirred at RT for 1 h. It was concentrated under reduced pressure. The residue was in dissolved in 20 mL of DCM and cooled with an ice bath, then treated with DEIA (1.47 mL, 8.47 mmol) followed by acryloyl chloride (0.16 mL, 2.03 mmol). After 20 min at 0° C., additional acryloyl chloride (80 μL) was added in. The resulting mixture was stirred for 5 min, then quenched with 0.5 N NaOH (10 mL). The layers were separated and the water layer was extracted with 50 mL of DCM. The combined DCM extracts were washed with 2×5 mL of brine, dried over Na2SO4 and concentrated. The residue was stirred in 25 mL of EtOAc. The insoluble solid was filtered and dried to give 310 mg of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11a). The filtrate was concentrated and purified on a silica gel column (35-100% EtOAc in hexanes) to give 140 mg of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11a). m/z (ESI, +ve ion) 338.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (1H, s), 8.95 (1H, s), 8.05 (1H, d, J=9.6 Hz), 7.68 (2H, m), 7.49 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=8.2 Hz), 6.72 (1H, d, J=9.6 Hz), 6.46 (1H, dd, J=17.0, 10.2 Hz), 6.26 (1H, d, J=16.8 Hz), 5.78 (1H, d, J=9.6 Hz), 2.20 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.CCO>CCOC(C)=O>[Cl:12][C:5]1[C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]2[N:1]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCO)cc1
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCc1ccc(-n2c(-c3ccccn3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (1.83 g, 5.54 mmol), 2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), and EtOH (40 ml) was refluxed for 1 hour. After cooling to room temperature, the solvent was removed. The residue was dissolved with benzene (50 ml) and treated with Pb(OAc)4 (3.38 g, 6.10 mmol) at room temperature for 1 hour. The mixture was diluted with EtOAc and the solution was washed with sat. NaHCO3 aq. and brine. The organic fraction was dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with hexane/EtOAc=5/2 to afford 1.20 g (52%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].N1C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:23])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
8.84 g (32.0 mmol) of t-butyl 4-(4-aminophenyl)-piperidine-1-carboxylate were dissolved in 150ml of methylene chloride and treated with 3.82 g (35.2 mmol) of ethyl chloroformate in the presence of 2.78 g (35.2 mmol) of pyridine. The reaction mixture was stirred at room temperature for 16 hours. Thereafter, it was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The residue (11.3 g) was chromatographed on 95 g of silica gel 60 with ether/n-hexane (4:6). After recrystallization from ether/n-hexane there were obtained 6.15 g of t-butyl 4-(4-ethoxycarbonylamino-phenyl)-piperidine-1-carboxylate. M.p.: 126°-128°.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH:8](=O)/[CH:9]=[CH:10]/[CH3:11]>C(O)C>[CH2:8]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH:9]=[CH:10][CH3:11]
Reactant: C/C=C/C=O
Reactant: COC(CN)OC
Solvent: CCO
Product: CC=CCNCC(OC)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
200 g of molecular sieve are initially introduced into 1,000 ml of ethanol and 105 g (1 mol) of aminoacetaldehyde dimethyl acetal and 70 g (1 mol) of crotonaldehyde are added. The mixture is allowed to stand at room temperature overnight, decanted off from molecular sieve and cooled to 0° C., and 40 g of sodium borohydride are added in 1 g portions. The mixture is then stirred overnight at room temperature and concentrated, the residue is taken up in 500 ml of water and potassium carbonate is added until an organic phase separates. This is extracted using chloroform, dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl-].C([Al+2])C.[CH:16]([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:17]>ClCCCl.CCCCCC>[C:19]1([S:18][CH:16]2[CH2:17][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]2[C:1]([O:9][CH3:10])=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CSc1ccccc1
Reactant: COC(=O)/C=C/C(=O)OC
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: COC(=O)C1CC(Sc2ccccc2)C1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 1.06 g (7.34 mmol) of dimethyl fumarate in 20 mL of dry 1,2-dichloroethane under nitrogen atmosphere, was added with stirring, 7.34 mmol of a 1.0 M solution of ethylaluminum dichloride in hexane. The resultant yellow solution was heated to reflux and a solution of 1.0 g (7.34 mmol) of phenyl vinyl sulfide in 4 mL of dry 1,2-dichloroethane was added dropwise, via syringe, over a period of 20 minutes. The reaction mixture was allowed to stir at reflux for 3 h. After cooling to ambient temperature, the reaction was quenched carefully with 100 mL of 1.0 N hydrochloric acid solution and the reaction mixture was extracted with 3×50 mL of ethyl acetate. The organic extract was washed with 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a viscous orange oil. The oil (1.56 g) was chromatographed on silica gel (25 g) eluted with 300 mL of 3% ethyl acetate in 1,2-dichloroethane. The resultant yellow oil was purified by bulb-to-bulb distillation to give the title compound as a yellow oil; b.p 120° C. (0.05 mm Hg); EI-MS, m/e (relative intensity): 280 (M+, 18), 136 (100), 91 (13); 1H NMR (CDCl3) δ2.20 (q, 1H), 2.61 (m, 1H), 3.22 (q, 1H), 3.34 (t, 1H), 3.66 (s, 3H), 3.67 (s, 3H), 3.87 (m, 1H), 7.30 (m, 5H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[O:12][C:13]2[C:14](=[C:16]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:15]=1)(=[O:10])[CH3:9].[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>ClCCl>[C:8]([C:11]1[O:12][C:13]2[C:14](=[C:16]([S:22]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:15]=1)(=[O:10])[CH3:9]
Reactant: COc1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Reactant: NCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NCc2cccnc2)c2cc(C(C)=O)oc12

Procedure:
Triethylamine (0.43 ml) was added to a solution of 2-acetyl-7-methoxy-4-benzofuransulphonyl chloride (600 mg) and 3-(aminomethyl)pyridine (0.25 ml) in dichloromethane at room temperature. The resultant mixture was stirred for 20 hours and then diluted with dichloromethane (20 ml). The solution was washed with water (20 ml) and brine (20 ml) and dried (MgSO4). Concentration in vacuo provided a dark oil which was applied to a silica column and eluted with 2% methanol in dichloromethane. The title compound was obtained as a pale yellow solid (161 mg). Mp 168°-170° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([O:16][CH2:17]C)=[O:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)=[O:2].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](OC2C=CC=CC=2)=[O:31])[N:22]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([O:20][CH3:19])[N:22]=[C:23]([NH:29][C:30]([NH:13][S:10]([C:8]2[CH:9]=[C:4]([NH:3][CH:1]=[O:2])[CH:5]=[CH:6][C:7]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:12])=[O:31])[N:24]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOC(=O)c1ccc(NC=O)cc1S(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
1.00 g of 5-formylamino-2-ethoxycarbonylbenzenesulfonamide, 1.11 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine and 0.82 ml of DBU in acetonitrile are reacted analogously to Chemical Example A.1; Yield: 1.00 g, M.p.: 113° to 118° C. (dec.), Mass spectrum (CI):(M+l) =454
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: O
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. Melting Point: 115-118° C. (water)
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]=[C:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.CN(C)C=O.[H][H]>[Pd].CO>[CH2:3]([CH:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH:2]([CH3:21])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21

Procedure:
2.8 g of a mixture of 10-(2-methyl-1-propenyl)-5H,10H-imidazo[1,2-]indeno[1,2-e]pyrazin-4-one and 10-(2-methylpropylidene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are hydrogenated in the presence of 180 ml of dimethylformamide, 20 ml of methanol and 0.5 g of 10% palladium on charcoal for 22 hours at 50° C. and at a pressure of 54 bar of hydrogen. After filtration of the catalyst under inert atmosphere, the solvents are evaporated off and the grey solid obtained (2.1 g) is purified by chromatography on a column of silica (180 g partially deactivated with 3 ml of water), using a mixture of dichloromethane and methanol (90/10 by volume) as eluent. After trituration in 20 ml of ethyl ether, filtration and drying at 100° C., 1.2 g of 10-isobutyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, in the form of a cream-coloured solid melting above 260° C. (Analysis % calculated C: 73.10, H: 6.13, N: 15.04, O: 5.73, % found C: 72.9, H: 5.6, N: 14.8).
Reaction SMILES: C([Mg]Br)C.C(OCC)C.I[C:11]1[N:12]=[C:13]2[CH2:19][CH2:18][O:17][C:16]3[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=[N:23][C:15]=3[N:14]2[C:28]=1[I:29].O1CCCC1>[NH4+].[Cl-]>[I:29][C:28]1[N:14]2[C:15]3[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]2=[N:12][CH:11]=1
Reactant: COC(=O)c1cnc2c(c1)OCCc1nc(I)c(I)n1-2
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cnc2c(c1)OCCc1ncc(I)n1-2
Reaction time: 0.29 h

Procedure:
Ethylmagnesium bromide in ethyl ether (3.0 M, 0.104 mL, 0.31 mmol)) was added dropwise to a suspension of methyl 9,10-diiodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate (130 mg, 0.26 mmol) in Tetrahydrofuran (5.0 mL, 62 mmol) at −15° C. The mixture was stirred for 15-20 min (a completion was monitored by LCMS), pour into 20 ml of sat. aq. NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water (2×20 ml), brine, dried over MgSO4 and concentrated in vacuum. Weight 92 mg (94%). MS (ESI+): 372.0.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([C:26]4[N:27]=[CH:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(Cl)(=O)OC(Cl)C>ClC(Cl)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([C:21]2[CH:20]=[C:19]([NH:18][C:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[N:11]=[CH:12][N:13]=3)[CH:24]=[CH:23][C:22]=2[CH3:25])[N:27]=1
Reactant: Cc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1-c1cc2ccccc2cn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Cc1ccc(Nc2ncnc3c2CCNC3)cc1-c1cc2ccccc2cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 7-benzyl-N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (500 mg, 1.09 mmol) in dichloroethane (14 ml) is added DIEA (284 mg, 2.2 mmol) and 1-chloroethyl carbonochloridate (313 mg, 2.2 mmol). The reaction mixture is stirred at 90° C. for 12 hours, and cooled. The solvent is removed by rotary evaporation. The residue is redissolved in methanol (20 ml) and stirred at room temperature for 15 hours. After concentration, the crude product is purified by silica gel flash chromatography (eluted with 5% methanol in ethyl acetate) to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a dark yellow solid. LC-MS m/z: 368.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31](=O)[CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:31][CH3:32])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(OCCO)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(OCCO)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a stirred solution of methyl 3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(2-hydroxyethoxy)-2-methylbenzoate (2.0 g, 4.7 mmol) and acetaldehyde (0.63 g, 14.2 mmol) in dichloroethane (20 mL) was added acetic acid (1.7 g, 28 mmol) and the reaction mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (3.0 g, 14.2 mmol) was added at 0° C. and reaction was stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase was separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure; Crude material was purified by column chromatography to afford the title compound (1.9 g, 89%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.NC(N)=O.[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)Cl>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: C1=CSCC1
Agent: NC(N)=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccs1
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
2-H-thiophene-urea (85 mg, 0.27 mmol), available from Step C of Preparative Example 16.3, was partially dissolved in methylene chloride (4 mL and added dropwise to a stirred solution of chlorosulfonic acid (0.09 mL, 1.35 mmol) in 4 mL of methylene chloride at room temperature. After 10 min, the mixture was poured into crushed ice and extracted with ethyl acetate several times. The extracts were washed with water and brine, dried with sodium sulfate, and concentrated to give the corresponding thiophene sulfonyl chloride as a greenish oil (45 mg) used in next step directly.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH2:10]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCc2ccccc2)nc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 40.3 %

Procedure:
To a stirred solution of 6-chloronicotinonitrile (1 g, 7.2 mmol) and benzyl alcohol (780 mg, 7.2 mmol) in toluene (15 mL) was added KOH (729 mg, 12.99 mmol) and 18 crown ether (2.86 g, 10.8 mmol). The resulting mixture was stirred at 70° C. for 7 hrs. The mixture was diluted with cold water and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure. The obtained residue was purified by column chromatography (using neutral alumina and 5% MeOH: CHCl3 as eluent) to afford 610 mg (40.1% yield) of 6-benzyloxy-nicotinonitrile. LCMS Purity: 77.69%.
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([C:25]#[CH:26])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1OS(C)(=O)=O)(=O)C.C1CN2C(=NCCC2)C1.CO>CC#N>[C:25]([C@:6]1([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)#[CH:26]
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: C1CN=C2CCCN2C1
Solvent: CO
Solvent: CC#N
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Reaction time: 12 h

Procedure:
A mixture of 13 (105 mg, 0.272 mmol) and DBN (101 μL, 0.815 mmol) in CH3CN (10 mL) was refluxed for 11 h. After being quenched with AcOH, the reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). The product, obtained after purification by silica gel column chromatography (hexane/EtOAc=1/1) of the organic layer, was dissolved in saturated NH3 in MeOH (30 mL), and kept at room temperature for 12 h. Evaporation of the solvent followed by preparative TLC (hexane/EtOAc=1/1) purification gave TKD-4-114 (49.6 mg, 74%) as a solid: mp 207-209° C.; UV (MeOH) λmax 264 nm (ε10800), λmin 235 nm (ε4800); 1H NMR (CDCl3) δ1.83 (3H, s, Me), 2.63 (1H, s, ethynyl), 3.47 (1H, br, OH), 3.88 (1H, d, Jgem=12.5 Hz, H-5′a), 3.96 (1H, d, Jgem=12.5 Hz, H-5′b), 5.91 (1H, dd, J1′,2′=1.1 Hz and J2′,3′=5.9 Hz, H-2′), 6.30 (1H, dd, J1′,3′=2.0 Hz and J2′,3′=5.9 Hz, H-3′), 7.16-7.17 (1H, m, H-1′), 7.44 (1H, d, J6,Me=1.1 Hz, H-6), 9.06 (1H, br, NH); FAB-MS m/z 249 (M++H). Anal. Calcd for C12H12N2O4.⅙H2O: C, 57.37; H, 4.95; N, 11.15. Found: C, 57.36; H, 4.69; N, 10.98.