Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19](O)=[O:20])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29][NH2:30].C(Cl)CCl.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=2)=[O:20])=[C:9]1[CH:22]([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COc1cc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 8, 6.0 mg, 0.019 mmol) and 3,4-difluorobenzylamine (7.0 I, 0.057 mmol) in CH2Cl2 (1.0 ml) was added EDC (5.5 mg, 0.029 mmol), DMAP (3.5 mg, 0.029 mmol), and Et3N (25 l). The mixture was stirred at room temperature for 16 h and was directly purified by preparative thin layer chromatography (PTLC) on silica gel (50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:30]=[CH:29][C:20]([CH:21]=[C:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:19][CH:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:30]=[CH:29][C:20]([CH:21]=[C:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:19][CH:18]=3)[N:14]=2)[NH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C4SC(=O)NC4=O)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C4SC(=O)NC4=O)cc3)nc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
In a 35 ml vial, 5-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)thiazolidine-2,4-dione (0.100 g, 0.0001 mole) was taken in 8 ml CH2Cl2 and cooled to 0° C. under N2 atm. TFA (2 ml, 0.0268 mole) was added dropwise at 0° C. and the reaction mixture was stirred for 16 h at room temperature. After completion of the reaction, solvent was evaporated under reduced pressure from the reaction mixture and saturated NaHCO3 solution was added dropwise to make Ph basic. The solid that precipitated out was washed with water and pentane and 0.050 g of the solid was taken up in ethanol (20 ml) and NaOAc.3H2O (0.246 g, 0.0018 mole) was added. The reaction mixture was stirred at room temperature for 16 hr. Ethanol was evaporated under reduced pressure and the solid was washed with water and pentane. The crude compound was purified by triturating with pentane to yield 0.018 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2=[N:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)([CH3:23])[CH3:22])[C:12]=3[OH:31])[N:10]=[C:6]2[CH:5]=1)([OH:3])=[O:2].[C:34]1(C)C=CC=CC=1.CO.S(=O)(=O)(O)O>>[CH3:34][O:2][C:1]([C:4]1[CH:33]=[CH:32][C:7]2=[N:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:14]=[C:13]([C:21]([C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=4)([CH3:23])[CH3:22])[C:12]=3[OH:31])[N:10]=[C:6]2[CH:5]=1)=[O:3]
Reactant: CC(C)(C)c1cc(-n2nc3ccc(C(=O)O)cc3n2)c(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)c4ccc(Cl)cc4)c3O)nc2c1

Procedure:
The compound prepared in Example 91 (6.0 g, 0.012 mol), toluene (15 g, 0.16 mol), methanol (100 g, 3.1 mol) and concentrated sulfuric acid (0.4 g, 0.004 mol) are added to a reaction flask and heated to reflux. After eight hours at reflux, the solvents are removed by distillation and the residue is dissolved in 200 g of toluene. The solution is then passed through an absorbent (silica gel) to remove residual acid. The toluene is distilled off and the residue is twice recrystallized from methanol. The title compound is obtained in a yield of 4.9 g as a light yellow powder melting at 93-104° C. whose structure is consistent with 1Hnmr and mass spectrometric analyses.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(=O)OCC>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([CH3:13])[CH:3]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cc(Br)c2ccccc2c1=O
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cn(C)c(=O)c3ccccc23)c1
Temperature: 90 °C
Yield: 16.7 %

Procedure:
A mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (100 mg, 0.42 mmol), and (3-methoxyphenyl)boronic acid (70 mg, 0.46 mmol), PPh3 (66 mg, 0.25 mmol), Na2CO3 (133 mg, 1.26 mmol), and Pd(dppf)Cl2 (62 mg, 0.084 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated overnight at 90° C. Extractive work up with ethyl acetate followed by preparative TLC (PE:EA=1:1) gave the title compound (18 mg, 0.07 mmol) as a white solid in 17% yield. 1H NMR (DMSO, 400 MHz): δ 8.30 (d, 1H, J=7.68), 7.68 (t, 1H, J=7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J=7.44), 6.97-7.00 (m, 3H), 3.78 (s, 3H), 3.54 (s, 3H). MS (m/z, relative intensity): 266 (M+, 1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:70]([CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:41][S:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:72])=[O:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](CSCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](CSCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
19.3 mg (20 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulfanyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 20) was dissolved in 1.2 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride, by analogy with the synthesis in Example 1. After lyophilization from dioxane, 8.6 mg (45% of the theoretical) of the title compound was obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2cc(OC)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)c2ccc(OC)cc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a mixture of (S)-2-(7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (100 mg, 0.31 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added K2CO3 (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (145 mg, 97%).
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[O:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH:20]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH3:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]1([S:7][N:22]([CH:20]([CH3:21])[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][C:12]3[CH:30]=[CH:31][CH:32]=[C:10]([Cl:9])[CH:11]=3)=[CH:15][CH:16]=2)[C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NC(C)COc1ccc(Oc2cccc(Cl)c2)cc1
Reactant: ClSc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N(Sc1ccccc1)C(C)COc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
A solution of 4 g of phenylsulfenyl chloride in 10 ml of toluene is added dropwise at 0°-5° C. in the course of 20 minutes to a solution of 9 g of ethyl 2-[4-(3-chlorophenoxy)phenoxy]-1-methylethylcarbamate in 30 ml of pyridine, with stirring, and the mixture is stirred for a further 15 hours at room temperature. Most of the pyridine and toluene is then distilled off in vacuo at a temperature of lower than 45° C., and the residue is poured into 300 ml of ice-water and extracted repeatedly with ether. The combined ether phases are first washed with cold, dilute hydrochloric acid and then with water, the mixture is dried over sodium sulfate, and the solvent is distilled off completely. The residue is purified further by chromatography on silica gel (eluent: n-hexane/diethyl ether, 19:1), by which process ethyl N-phenylthio-2-[4-(3-chlorophenoxy)phenoxy]-1-methylethylcarbamate is obtained as a colourless oil, nD20 : 1.5810.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](O)[CH:14]=[CH2:15]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:15][CH:14]=[CH2:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(OC)c1
Yield: 75 %

Procedure:
In a manner analogous to Example 1(a), 5 g (30 mmoles) of 4- hydroxy-3-methoxybenzoic acid treated at 100° C. for 4 hours with 50 ml of allyl alcohol and 820 μl of concentrated sulfuric acid, give 4.65 g (75% yield) of the expected ester in the form of a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=O)[C:5]([N:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C[O-].[Na+].O>C(=O)(OC)OC.CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:20][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCN(CC(C)C)c1ncc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: CO
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)cnc2N(CC(C)C)CC1
Temperature: 50 °C
Yield: 91.8 %

Procedure:
To a solution of methyl 4-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]butanoate (750 mg) in dimethyl carbonate (20 ml) was added a 28% sodium methoxide solution in methanol (810 mg), and the mixture was heated at 50° C. for 2 hours under a nitrogen atmosphere. The mixture was returned to room temperature, water was added thereto and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=6:1) to give methyl 3-bromo-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate (654 mg) as a yellow oily material.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-])=O)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]>CO.[Fe]>[ClH:1].[NH2:13][C:7]1[CH:6]=[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:4]([O:3][CH3:2])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(C(N)=O)c(N)cc1OCCCN1CCCC1
Temperature: 50 °C
Yield: 85 %

Procedure:
Concentrated hydrochloric acid (5 ml) was added to a suspension of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (1.5 g, 4.64 mmol) in methanol (20 ml) and the mixture was heated at 50° C. to give a solution. Iron powder (1.3 g, 23.2 mmol) was added in portions and the reaction mixture was then heated at reflux for 1 hour. The mixture was allowed to cool, the insolubles were removed by filtration through diatomaceous earth and the volatiles were removed from the filtrate by evaporation. The residue was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with dilute hydrochloric acid (pH2). The fractions containing product were concentrated by evaporation and the resulting precipitate was collected by filtration and dried under vacuum over phosphorus pentoxide to give 2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide hydrochloride (1.44 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:1]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=3)[N:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(NCc3ccco3)c2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3ccco3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-[2-furylmethylamino]-6-dimethylaminoquinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.5 g of the title compound is obtained, m.p.: 143° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(O)(=O)C.[CH3:22][NH2:23]>O>[CH3:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)O
Product: CNc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]

Procedure:
A solution of 20.0 g (0.0776 mol) of 4-(4-chloro-3-nitrophenyl)-4-oxobutanoic acid in 200 ml of 40% aqueous methylamine solution was stirred for 3 hours in a sealed vessel. Then the mixture was diluted with the same volume of water and acidified with acetic acid. The product precipitated was suction filtered, thoroughly washed with water and dried at 50° C. in a circulating air dryer. 18.5 g (95% of theoretical) of the desired compound were obtained in the form of yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>CCO.O>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)=[CH:31][N:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: CSc1ccc(Cc2cnc(F)c(B(O)O)c2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(SC)cc4)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.37 g, 6.15 mmol), 2-fluoro-5-(4-(methylthio)benzyl)pyridin-3-ylboronic acid (1.89 g, 6.83 mmol), Am-Phos (224 mg, 0.316 mmol), and potassium acetate (2.72 g, 27.7 mmol) were suspended in EtOH (30 mL) and water (7.5 mL). Nitrogen was bubbled through the suspension for about 20 seconds, and then the flask was fitted with a reflux condenser and put in a preheated oil bath (80° C.-88° C.) and the reaction was stirred under nitrogen for 2 hours and 45 minutes. Then, the reaction was cooled to room temperature, treated with water (90 mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated. The residue was washed with hexanes, but the hexanes rinsings still contained product. So, these rinsings were combined with the residue and concentrated. The material was purified on a silica gel filter (600 mL fritted filter funnel with about 3 inches of silica gel; 5:1 DCM/hexanes to DCM to 40:1 DCM/MeOH to 30:1 DCM/MeOH) to give 4-(2-fluoro-5-(4-(methylthio)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.843 g). 1H NMR (CDCl3, 400 MHz) δ 8.32 (dd, J=9.00 Hz, 2.35 Hz, 1H), 8.14 (dd, J=1.56 Hz, 1H), 7.24-7.18 (m, 6H), 7.13-7.09 (m, 2H), 6.90-6.83 (m, 4H), 4.81 (s, 2H), 4.78 (s, 2H), 3.99 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.53 (s, 3H), 2.46 (s, 3H). m/z (ESI, pos. ion) 582 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].O1CCC[CH2:12]1>>[CH3:1][O:2][C:3]([C:5]1([O:8][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1(OC)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1-Hydroxy-cyclopropanecarboxylic acid methyl ester (1.1 6 gm, 10 mmol) was dissolved in 10 ml of tetrahydrofuran and cooled under a nitrogen atmosphere to 0° C. Sodium hydride (0.52 gm, 60% oil dispersion) was added portionwise followed by lodomethane (1 ml) and stirred for 18 hrs. The reaction mixture was quenched with ammonium chloride and extracted with ethylacetate to obtain 2 gm of title product. (MH+=130)
Reaction SMILES: [I-:1].[Na+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>C(O)CCCC.[Cu](I)I>[I:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: [I-]
Reactant: CC(C)CCc1ccccc1Br
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCO
Product: CC(C)CCc1ccccc1I
Temperature: 130 °C
Yield: 84 %

Procedure:
Charge a pressure tube with sodium iodide (734 mg, 4.9 mmol), copper iodide (23 mg, 0.12 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (34 mg, 0.24 mmol) dissolved in 0.5 ml of pentanol, and 1-bromo-2-(3-methyl-butyl)-benzene dissolved in 0.5 ml of pentanol. Purge with nitrogen, cap the tube, and heat at 130° C. for 3 days. Subject to silica gel chromatography, eluting with hexane to obtain the desired compound as a colorless liquid (587 mg, 84%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[CH:29][C:28](=[O:31])[N:27]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>C(Cl)Cl.CO>[ClH:37].[CH:32]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[CH:29][C:28]2=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=c1ccc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
A solution of 4-[6-(8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (143 mg, 0.29 mmol) in CH2Cl2/MeOH (6 mL/1.5 mL) was treated with HCl gas at room temperature for ˜3 min. The solution was stirred at room temperature for ˜6 hours then filtered to collect the solid. This solid was washed with CH2Cl2 and dried in vacuo to yield 8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (98 mg, 66%). mp 213–215° C. Anal Calc'd for C21H25N7O2O HCl 2.5 H2O: C, 49.51; H, 5.90; N, 15.74; N, 15.74; Cl, 13.92. Found: C, 49.64; H, 6.12; N, 19.23, Cl, 14.20.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=2)[N:7]=1.[F:15][C:16]1[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([F:26])[C:17]=1[C:27]1[S:31][C:30]([NH2:32])=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([F:26])[C:17]=1[C:27]1[S:31][C:30]([NH:32][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[N:10]=3)[N:7]=2)=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)c1cn2nc(Cl)ccc2n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nc(C(C)(C)O)cn4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)propan-2-ol (258 mg, 1.22 mmol) and 5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-amino-thiophene-3-carboxamide (90 mg, 0.31 mmol) as starting materials.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[C:13]([OH:20])=[C:14]([NH:19][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O)Nc1cccc(Cl)c1Cl
Yield: 11.7 %

Procedure:
A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (54 mg, 0.17 mmol) and 2,3-dichlorophenylisocyanate (34 μL, 0.26 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), gave the desired product (10 mg, 12%). EI-MS (m/z) 498.2, 500.1, 502.1 (M−).