Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:28]3[CH2:29][CH2:30][CH2:31][CH:26]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:20][CH:21]=4)[C:27]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (131.2 mg, 0.5 mmol) and of 2-bromo-6-phenyl-cyclohexanone (139.2 mg, 0.55 mmol) in ethanol (5 mL) was stirred at room temperature over the weekend. A clear yellow solution was obtained which was heated over night to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (110 mg, 53%) as a white solid. MS ISP (m/e): 417.5 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.19 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.27 (t, 2H), 7.11-7.18 (m, 4H), 6.95 (s, 1H), 6.71 (d, 1H), 3.98 (m, 1H), 3.34 (s, 3H), 2.73 (m, 2.14 (m, 1H), 2.10 (s, 3H), 1.70-1.91 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]([Cl:40])=[CH:22][N:21]=1>>[Cl:40][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: Cc1cccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Product: Cc1cccnc1-c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 58 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine) was combined with (2,5-Dichloro-pyrimidin-4-yl)-[2-(3-methyl-pyridin-2-yl)-phenyl]-amine to yield 5-Chloro-N*4*-[2-(3-methyl-pyridin-2-yl)-phenyl]-N*2*-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-pyrimidine-2,4-diamine (93.00 mg, 58% yield) as an off white powder. 1H-NMR (CDCl3) δ 9.45 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.38 (m, 3H), 7.24 (m, 2H), 7.02 (d, J=8.0 Hz, 1H) 6.87 (m, 1H), 3.24 (m, 7H), 2.34 (s, 3H), 1.31 (m, 3H). LC/MS (ESI+)=553 (M+H). MP=130.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:14])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 46 h

Procedure:
1.65 g (8.49 mmol) of N-methyl-4-methyl-3-nitrobenzamide was dissolved into 9.9 mL of DMF and 6.49 g (50.90 mmol) of N,N-dimethylformamide dimethylacetal was added dropwise to this solution under a nitrogen atmosphere at room temperature, and the reaction mixture was heated and stirred at 80° C. for 46 hours.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:6]=2[C:7]=1[CH3:8])=[O:2].[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[CH:15]1([CH:1]([OH:2])[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1c(C=O)oc2ccc(C#N)cc12
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(C#N)cc12
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution (30 mL) of 2-formyl-3-methyl-1-benzofuran-5-carbonitrile (1.49 g) synthesized above in tetrahydrofuran was added a 1.0M solution (12.1 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane), and then purified by NH silica gel column chromatography (ethyl acetate) to give the title object compound (922 mg, 43%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OB(O)c1ccoc1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)C1
Product: OC1CCCC(Nc2ccc3ncc(-c4ccnc(-c5ccoc5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3RS)-3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate R) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].Br[C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Reactant: Cn1ccnc1Br
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)N(c2nccn2C)CC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Yield: 19.1 %

Procedure:
To a stirred mixture of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (91 mg, 0.3 mmol) (prepared as described in Example 28) and 2-bromo-1-methyl-1H-imidazole (48.3 mg, 0.3 mmol) in 1,4-dioxane (6 ml) was added potassium phosphate (318 mg, 1.5 mmol), copper (I) iodide (57.1 mg, 0.3 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.047 ml, 0.3 mmol) and the mixture was heated at reflux under argon for 3 hours. The mixture was cooled to room temperature and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic extracts were separated, washed with water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxamide (22 mg, 19%). LC/MS [M+H]+=384, retention time=1.69 minutes.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:5][C:6]([O:8]C)=O.[OH-].[Na+].[C:16](O)(=O)[CH3:17].C(=O)C.[BH4-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:16]([N:2]1[C:6](=[O:8])[CH2:5][CH2:4][C@H:3]1[C:10]([O:12][CH3:13])=[O:11])[CH3:17]
Reactant: CC(=O)O
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: CC=O
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN1C(=O)CC[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
Dimethyl L-glutamate hydrochloride (0.500 g, 2.37 mmol) was dissolved in methanol (4 ml) and tetrahydrofuran (8 ml) and the mixture was then treated with crushed sodium hydroxide (0.099 g, 2.49 mmol) for 10 minutes. At this stage acetic acid (0.136 ml, 2.37 mmol) and acetaldehyde (0.199 ml, 3.55 mmol) were added together to the mixture as a solution in tetrahydrofuran (1 ml). After stirring for 10 minutes the mixture was cooled to 0° C. and treated with sodium borohydride pellets (0.088 g, 2.37 mmol). The mixture was then left to warm to room temperature. Once the mixture had reached room temperature it was diluted with ethyl acetate (30 ml) and washed with saturated aqueous sodium hydrogen carbonate, filtered through a phase separator (with stirring) and evaporated to give an oily residue. The oil was dissolved in toluene and heated at reflux for 4 hrs. To ensure complete reaction the mixture was then heated overnight at reflux. The solvent was then evaporated and the resulting residue was purified by flash-silica column chromatography, eluting with a gradient of 30-50% ethyl acetate in hexane, to give crude methyl 1-ethyl-5-oxo-prolinate (0.135 g) as a clear oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:13][C:14]([C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[CH:19][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[N:17]=1)=O)([CH3:12])[C:3](=[O:11])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][C:2]1([CH3:12])[C:3](=[O:11])[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([C:16]2[C:21](=[O:22])[C:20]([O:23][CH3:24])=[CH:19][N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[N:17]=2)=[N:13]1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)NC(C)(C)C(=O)Nc2ccccc2)c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C2=NC(C)(C)C(=O)N2c2ccccc2)c1=O
Temperature: 25 °C
Yield: 27.1 %

Procedure:
A mixture of N-[1,1-dimethyl-2-oxo-2-(phenylamino)ethyl]-5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (142 mg), sodium acetate (74 mg) and acetic acid (1 mL) was irradiated with microwave at 120° C. for 2 hr. After cooling to room temperature, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (37 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].[Br:20][C:21]([Br:25])=[CH:22][CH2:23]Br>CN(C)C=O>[Br:20][C:21]([Br:25])=[CH:22][CH2:23][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Reactant: BrCC=C(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Br)Br)Cc1ccc(OC(F)(F)F)cc1
Yield: 43.9 %

Procedure:
Using 0.20 g of (4-(trifluoromethoxy)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 50 mg of sodium hydride (60% in oil), and 0.46 g of 1,1,3-tribromopropene, and according to the process described in the Production Example 1, there was obtained 0.16 g of 2-(3,3-dibromo-2-propenyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (29)).
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[CH3:19][CH:20]1OC(C)OC(C)O1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH3:19][CH:20]1[O:12][C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][O:2]1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reactant: CC1OC(C)OC(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1OCC(C(=O)c2ccccc2)(c2ccccc2)O1
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
A solution of 10.0 grams (41 millimoles)αmethylol benzoin, 20.0 grams (45 millimoles) paraldehyde, 0.5 grams p-toluenesulfonic acid and 100 ml. benzene was heated with magnetic stirring to 80°-90° C for 30 minutes under a Dean-Stark trap under conditions such that refluxing occurred, but the vapors condensed before reaching the trap. The temperature of the reaction mixture was then gradually raised to 120°-130° C and 8 ml. water was collected. The reaction mixture was then saturated with ammonia gas, the resulting salt precipitate removed by filtration on a Buchner funnel to provide a benzene solution of the reaction product. The benzene solvent was removed under vacuum. A yield of 11.8 grams of a yellow oil was obtained. The yellow oil was chromatographed on silica gel with 5% ethyl ether in n-hexane elution to provide 9.5 grams of an odorous yellow oil which distilled at 125°-130° C at 20μ vacuum pressure to provide 6.5 grams of a light yellow oil product.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([F:24])[C:16]=1F.[Cl-].[NH4+]>C1COCC1>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([F:24])[C:16]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Diethyl malonate (44.8 g, 280 mmol) was added to a suspension of sodium hydride (60%, oil, 28.0 g, 700 mmol) in THF (280 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Then, 1,2,3-trifluoro-5-nitrobenzene (24.79 g, 140 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate (×2). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give diethyl 2,6-difluoro-4-nitrophenylmalonate (42 g) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][O:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:33])[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:24][C:22]1[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[C:20]([CH3:33])[N:19]=[C:18]([O:17][CH2:16][C:15]([N:14]([CH3:35])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:34])[N:23]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Pd—C (371 mg) was added to a solution of Compound 30 (3.7 g) in methanol (111 mL) and then, hydrogenation was carried out by stirring the mixture at atmospheric pressure and room temperature overnight. Subsequently, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 2.9 g (96% yield) of the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:17]([N+:18]([O-])=O)=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH:22][C:23]1[CH:33]=[CH:32][C:26]([C:27](=N)OCC)=[CH:25][CH:24]=1>CO>[CH:1]1([N:7]2[C:8]3=[N:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[C:17]3[N:18]=[C:27]2[C:26]2[CH:32]=[CH:33][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: CCOC(=N)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A solution of intermediate 58 (5.0 g, 20.0 mmol) and ethyl 4-hydroxybenzimidate hydrochloride (6.0 g, 30.0 mmol) in methanol (67 mL) was heated at reflux for 22 h. The reaction mixture was then cooled to rt and the precipitated solid was collected by vacuum filtration and washed sparingly with cold methanol to afford intermediate 59 as a white solid (6.13 g, 88%). ESI-MS m/e 352.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].[I-].[Na+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCN(C)C)c2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of 6-bromo-1H-indole-3-carboxylic acid methyl ester (500 mg, 1.97 mmol), sodium hydride (60% in mineral oil, 748 mg, 31.2 mmol), sodium iodide (295 mg, 1.96 mmol), 2-dimethylaminoethyl chloride hydrochloride (341 mg, 2.37 mmol) and DMF (60 mL) is heated at 100° C. for 8 hours. The reaction mixture is cooled, filtered, and the solids are washed with water and air dried. The solids are dissolved in MeOH (200 mL) and (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 20 mL) is added over several minutes. The reaction mixture is stirred for one hour and concentrated under reduced pressure. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is separated and dried over MgSO4. The crude product is purified via radial chromatography using 2.5% MeOH/CH2Cl2 to afford the title compound (195 mg, 30%). ES/MS m/e 327.0 (M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:19][CH2:18][CH2:17][C@@H:15]2[CH2:16][C@@H:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=3)[CH2:9][CH2:10]2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 0 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (176 mg, 0.63 mmol) from. Step 6, Example 2 was dissolved in dichloromethane (3 mL), then added triethylamine (190 mg, 1.87 mmol), 4-dimethylaminopyridine (15.3 mg, 0.13 mmol), last tosylchloride (167 mg, 0.87 mmol), stirred under N2 for 1.5 hours. The reaction solution was poured into ice water (10 mL), extracted with dichloromethane (10 mL×2). The organic phase was combined and dried by magnesium sulfate, filtered, then concentrated and purified by column chromatography through a 24 gram RediSep Rf™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[O:6][C:5](=[O:18])[CH:4]=1.[F:19][C:20]1[C:25]([C:26](Cl)=[O:27])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=1[F:32]>>[CH2:14]([N:13]([CH2:16][CH3:17])[C:9]1[CH:8]=[C:7]2[C:12]([C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]3[C:24]([F:29])=[C:23]([F:30])[C:22]([F:31])=[C:21]([F:32])[C:20]=3[F:19])=[CH:4][C:5](=[O:18])[O:6]2)=[CH:11][CH:10]=1)[CH3:15]
Reactant: CCN(CC)c1ccc2c(CN)cc(=O)oc2c1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Product: CCN(CC)c1ccc2c(CNC(=O)c3c(F)c(F)c(F)c(F)c3F)cc(=O)oc2c1

Procedure:
4-Aminomethyl-7-diethylaminocoumarin (50 mg, 0.2 mmol) is treated with pentafluorobenzoyl chloride (0.5 mL, 0.3 mmol) at 0° C. under dry argon protection, and worked up according to the procedure of Example 25. Compound 29 is obtained as an off-white solid (67 mg, yield: 76%).
Reaction SMILES: COC1C=C(C(C=O)=O)C=CC=1OC.CO.[NH2:17][C:18]1[N:27]=[C:26]([O:28][CH2:29]C)[C:25]2[C:20](=[N:21][C:22]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)=[CH:23][N:24]=2)[N:19]=1>C(O)(C)C>[NH2:17][C:18]1[N:27]=[C:26]([O:28][CH3:29])[C:25]2[C:20](=[N:21][C:22]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)=[CH:23][N:24]=2)[N:19]=1
Reactant: CCOc1nc(N)nc2nc(-c3ccc(OC)c(OC)c3)cnc12
Agent: COc1ccc(C(=O)C=O)cc1OC
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(-c2cnc3c(OC)nc(N)nc3n2)cc1OC

Procedure:
The sequence of reactions described in examples 53 to 57 was followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4-methoxyphenylglyoxal in the first step, and from methanol instead if isopropanol in the last step. This provided 2-amino-4-ethoxy-7-(3,4-dimethoxyphenyl) pteridine, a compound which was further characterized by its mass spectrum: 314 ([M+H]+, 100), 300 ([M+H-methane]+, 20).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:6].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[CH:16]=[C:15]([NH:17][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH3:22])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)O
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC)c1

Procedure:
By the procedure similar to that described in Example 23, 2-(2'-methoxybenzamido)-4-aminobenzoic acid and 2-methoxybenzoylchloride were reacted and treated to obtain crude crystals. Recrystallization from aqueous alcohol gave 2,4-bis(2'-methoxybenzamido)-benzoic acid having a melting point between 232° - 233°C which was identical to that obtained in Example 10.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)C=CC=CC=1>O>[C:1]1([S:7]([NH:10][NH:11][C:12](=[O:25])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C#Cc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: CC(C)(C)CCc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1

Procedure:
Example 38 was synthesized in accordance with the methods of Example 33, except that 4-(3,3-dimethyl-1-butynyl)benzoic acid, 2-(phenylsulfonyl)hydrazide (Example 37) was used instead of 4-phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide. MS: 361 (M+1 for C19H24N2O3S1); mp 168-169° C.; TLC (SiO2) Rf=0.7 (50% EtOAc/hexanes); HPLC (phenol hexal column, 1:1CH3CN/H2O+0.1% TFA) 99%, RT=16.8 min. 1H NMR (CDCl3) δ 0.95 (s, 9 H), 1.42-1.50 (m, 2H), 2.56-2.62 (m, 2H), 7.21-7.26 (m, 2H), 7.40-7.60 (m, 6H), 7.94 (d, 2H, J=7.8 Hz), 8.13-8.14 (m, 1H).