Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][C:20]=4[N:21]([CH2:24][O:25][CH2:26][CH3:27])[C:22]=3[CH:23]=2)[C:11](=[O:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCO.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:31][NH:30][CH2:29][CH2:28][C:20]=4[N:21]([CH2:24][O:25][CH2:26][CH3:27])[C:22]=3[CH:23]=2)[C:11](=[O:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-(ethoxymethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.20 mmol) in EtOH (2 mL) was added 1 N HCl in Et2O (1 mL). The reaction was stirred at 60° C. until complete. The solvent was concentrated and the residue was purified by preparative HPLC (Phenomenex Luna C18 (2), 250×50 mm, 15 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) to give 4-(benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one as a white solid (54 mg, 73%). The free base was converted to the HCl salt to give the title compound (35 mg, 65%) as a white powder: mp 148-149° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.49-7.37 (m, 5H), 7.08-7.05 (m, 1H), 6.14-6.12 (m, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.57 (s, 2H), 5.17 (s, 2H), 4.38 (m, 2H), 3.55 (m, 2H), 3.45-3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05 (m, 3H); ESI MS m/z 430 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.8 min.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Na].[NH2:6][CH2:7][C:8]([OH:10])=[O:9]>>[C:1]([CH2:2][CH2:3][N:6]([CH2:3][CH2:2][C:1]#[N:4])[CH2:7][C:8]([OH:10])=[O:9])#[N:4]
Reactant: NCC(=O)O
Reactant: C=CC#N
Agent: [Na]
Product: N#CCCN(CCC#N)CC(=O)O

Procedure:
Bis-cyanoethyl glycine was prepared in conventional manner by reacting two mols acrylonitrile with one mol sodium salt of glycine in essentially the same manner used in preparing the catalyst of Example 2, except that the sodium salt was neutralized at the end of the reaction.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=O.CC1(C)C(C)(C)OB([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:15]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:43])([F:44])[F:45])[CH:36]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25]
Reactant: CC1(C)OB(Cc2cccc(OC(F)(F)F)c2)OC1(C)C
Reactant: CC(C)CCc1c(Br)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)CCc1c(Cc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 85 °C
Yield: 29 %

Procedure:
To a solution of 3-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (See Compound 48, step 2, 60 mg, 0.144 mmol) in dioxane (4 mL) was added 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)benzyl)-1,3,2-dioxaborolane (90 mg, 0.288 mmol), Pd(dppf)Cl2 (10 mg) and aq. 2M K3PO4 (0.8 mL). The reaction was heated at 85° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated, dried to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(3-(trifluoromethoxy)benzyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 28.7% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.61 (s, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.19 (dd, J=25.5 and 8.5 Hz, 3H), 4.47 (s, 1H), 4.16 (s, 2H), 4.03-3.89 (m, 2H), 3.57 (s, 3H), 3.45 (dd, J=11.0 and 6.0 Hz, 2H), 3.12 (d, J=6.0 Hz, 2H), 1.81-1.64 (m, 2H), 1.51-1.56 (m, 1H), 1.03 (d, J=9.5 Hz, 2H), 0.81 (d, J=6.6 Hz, 6H). LCMS: MH+ 480 and TR=3.320 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Br:10])[CH:5]=[C:4]([F:11])[C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[H-].[Na+].Br[CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Br:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]([CH2:19]/[CH:20]=[CH:21]\[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13](=[O:15])[CH3:14]
Reactant: COc1c(Br)cc(F)c(NC(C)=O)c1Br
Reactant: CCOC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C\CN(C(C)=O)c1c(F)cc(Br)c(OC)c1Br
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To the solution of 8-6 (1.3 g, 3.82 mmol) in THF (20 mL) at room temperature was added NaH (100 mg, 4.2 mmol, dispersed in mineral oil, 60%). The mixture was stirred for 30 min until no gas was released. (E)-ethyl 4-brombut-2-enoate (0.88 g, 4.58 mmol) in THF (5 mL) was added. The mixture was stirred overnight at room temperature. TLC showed that the reaction was completed. Water was added to the reaction mixture and extracted with ethyl acetate (50 mL×3). The combined organic layers were combined and were concentrated in vacuo. The residue was purified by flash chromatography (silica gel, elution with ethyl acetate/petroleum=1:8 to 1:2) to afford 8-7 (1.6 g, 92.4%) as yellow oil.
Reaction SMILES: [CH3:1][C:2]([S:24][S:25][CH3:26])([CH3:23])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:9]([C:18](OCC)=[O:19])[CH:8]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C>[CH3:23][C:2]([S:24][S:25][CH3:26])([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:18][OH:19])[N:10]=[C:11]([CH2:13][OH:14])[CH:12]=1
Reactant: CCOC(=O)c1cc(OCCCC(C)(C)SSC)cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CSSC(C)(C)CCCOc1cc(CO)nc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
To a stirred solution of diethyl 4-(4-methyl-4-(methyldisulfanyl)pentyloxy)pyridine-2,6-dicarboxylate (5d) (270 mg, 0.672 mmol) in absolute ethanol (7.0 mL) was added calcium chloride (224 mg, 2.017 mmol) and sodium borohydride (76 mg, 2.017 mmol). The reaction was allowed to stir at ambient temperature for 90 minutes after which it was quenched with water and concentrated in vacuo to remove the ethanol. The mixture was then extracted twice with dichloromethane. The organic extracts were combined, washed with water, dried with anhydrous magnesium sulfate and filtered through celite. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel chromatography eluting with 10% methanol/dichloromethane to yield (4-(4-methyl-4-(methyldisulfanyl)pentyloxy)pyridine-2,6-diyl)dimethanol (5e)(75 mg, 35%); 1H NMR (400 Hz, CDCl3): δ 6.63 (s, 2H), 4.60 (s, 4H), 3.95 (t, 2H, J=6.2 Hz), 3.54 (bs, 2H), 2.35 (s, 3H), 1.82 (m, 2H), 1.66 (m, 2H), 1.26 (s, 6H); MS (m/z). found 340.1 (M+Na). See FIG. 5.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16](=[O:17])[C:15](=[O:18])[NH:14][C:13](=[S:19])[N:12]1[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N+]=[N-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:16](=[O:17])[C:15](=[O:18])[N:14]=[C:13]([S:19][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:12]1[CH3:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cn1c(=S)[nH]c(=O)c(=O)n1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1c(SC(c2ccccc2)c2ccccc2)nc(=O)c(=O)n1C(=O)OCc1ccccc1
Reaction time: 40 h

Procedure:
13.2 g of tetrahydro-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1(2H)-carboxylic acid benzyl ester are dissolved in 500 ml of ethyl acetate and treated with a solution of diphenyldiazomethane in 90 ml of low-boiling petroleum ether. The initially violet solution is left to stand for 40 hours at 25° C., the colour becoming pink. 3 ml of glacial acetic acid are added and, after 1 hour, the mixture is evaporated in vacuo at 40° C. A yellow oil is obtained as the evaporation residue. This is separated by column chromatography on silica gel using benzene, benzene/ethyl acetate (95:5) and benzene/ethyl acetate (90:10) for the elution. The fractions containing the desired substance are combined and evaporated in vacuo at 40° C. After recrystallization from ethanol, there is obtained colourless pure substance of m.p. 90°-92° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10](COCC[Si](C)(C)C)[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH:28]4[CH2:30][CH:29]4[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:41][CH2:42][CH3:43])[C:5]1=[O:44])[CH2:2][CH3:3].Cl>C(O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH:28]4[CH2:30][CH:29]4[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:41][CH2:42][CH3:43])[C:5]1=[O:44])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC4c4cccc(C(F)(F)F)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC4c4cccc(C(F)(F)F)c4)c3)nc2n(CCC)c1=O
Temperature: 85 °C

Procedure:
A mixture of 1,3-dipropyl-8-{1-[2-(3-trifluoromethyl-phenyl)-cyclopropylmethyl]-1H-pyrazol-4-yl}-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.55 g, 0.087 mmol), 2 N HCl (2 ml), ethanol (3 ml) were heated at 85° C. for 3 hours. The mixture was cooled to 10-15° C. and solid material was separated. It was filtered off and washed with water (1 ml), diethyl ether (1 ml) to obtain the title compound (0.016 g, 37
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:16][N:17]1[CH:21]([CH2:22][CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][N:19]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[C:18]1=[O:46].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:13])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][CH2:22][CH:21]2[CH2:20][N:19]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=3)[C:18](=[O:46])[N:17]2[CH3:16])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: COC(=O)C(C)(C)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
To a solution of 3-(4-Hydroxy-phenyl)-2,2-dimethyl-propionic acid methyl ester (31 mg, 0.15 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs2CO3 (64 mg, 0.19 mmol), and the mixture heated at 60° C. for 15 hours. The mixture is cooled, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO4), and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 2:1 hexanes:ethyl acetate to 1:4 hexanes:ethyl acetate) produced an oil (64 mg, 88%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: Fc1ccc2sc(CBr)nc2c1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(F)ccc3s1)c(=O)n2C
Yield: 98 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (156 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (3 ml). 2-bromomethyl-5-fluoro-1,3-benzothiazole (140 mg, 0.57 mmol), potassium carbonate (118 mg, 0.79 mmol) were added to give a reaction mixture. The obtained reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1b (240 mg, off-white solid), yield: 99%.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(=O)C(C)C)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 67.5 %

Procedure:
Following a procedure similar to that described in Example 74(a), but using 1.42 g of 2-butyl-4-isobutyrylimidazole-5-carbonitrile (prepared as described in Preparation 27), 4.49 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.76 g of potassium t-butoxide, 3.04 g of the title compound was obtained as crystals, melting at 115°-116° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[Cl:27])=[CH:15][C:16]=1[C:17]([NH2:19])=[O:18]>>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:14]1[S:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=2)=[C:16]([C:17]([NH2:19])=[O:18])[CH:15]=1
Reactant: COCc1cccc(Br)n1
Reactant: NC(=O)c1cc(-c2cc(Cl)ccc2Cl)sc1N
Product: COCc1cccc(Nc2sc(-c3cc(Cl)ccc3Cl)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 1 using 2-bromo-6-(methoxymethyl)pyridine (105 mg, 0.520 mmol) (for preparation, see Journal of Organic Chemistry 1993, 58, 4389-97) and 2-amino-5-(2,5-dichlorophenyl)thiophene-3-carboxamide (152 mg, 0.530 mmol) as starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16]C(O)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+]>C(O)(=O)C.[Pt]>[C:20]([O:23][CH2:16][NH:15][C:13](=[O:14])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: [Pt]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCNC(=O)CNC(=O)OCc1ccccc1
Yield: 60 %

Procedure:
Benzyloxycarbonylglycylglycine (3.99 g, 15 mmole) was suspended in a solution of anhydrous sodium acetate (0.9 g, 11 mmole) in glacial acetic acid (75 ml). The mixture was stirred and ice-cooled while being electrolysed (two 5 sq.cm. platinum foil electrodes placed 2 mm apart) using a current of 200-250 mA for 5 hours. The acetic acid was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with saturated sodium bicarbonate solution (5) ml portions, until the wash remained alkaline) and then with water (50 ml). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield the title compound as colourless crystals (1.85 g, 6.6 mmole).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH2:16][CH2:17][CH2:18][C:3]1=2.[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+]>CO>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:16]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=3[C:2](=[O:1])[C:3]=2[CH2:18][CH2:17]1
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester, m.p. 156°-158° C. (5.1 g) was reacted with 2-methyl benzaldehyde (3.3 g) in methanol (80 ml) in the presence of sodium methylate (2.28 g) under stirring at room temperature for 20 hours. The precipitate was filtered and washed with methanol and then with water until neutral: crystallization from CH2Cl2 -methanol gave 5.2 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester, m.p. 203°-205° C.
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:16]2[N:21]=[C:20]([NH:14][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:19]([F:23])=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(NC(c2ccccc2)c2ccccc2)nc1NC(c1ccccc1)c1ccccc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 1,1-diphenyl methylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2,N4-bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.91 (d, 1H, J=2.3 Hz), 7.39-7.25 (m, 20H), 6.51 (d, 1H, J=8.2 Hz), 5.77 (d, 1H, J=7.0 Hz); LCMS: ret. time: 33.46 min.; purity: 92%; MS (m/e): 461 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:4]=[N:3][CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cncnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cncnc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 27.3 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-5-ylcarbamate (263 mg, 0.972 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (238 mg, 0.972 mmol), diisopropylethylamine (0.169 ml, 0.972 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (97.4 mg, 27.4%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[CH2:26]([NH2:29])[C:27]#[CH:28].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH2:26][C:27]#[CH:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: C#CCN
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Preparation 19, 8 -chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-chloro-1-[[(2-propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 24 8 -Nitro-1-[[(2-propynyl)amino]methyl]-6(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](O)=[N:6][C:7]=1[CH3:8].[ClH:13]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5]([Cl:13])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(O)c(C#N)c(C)c1Br
Reactant: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)c(C)c1Br
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 9.0 grams (0.040 mole) of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine in 40 mL of phosphorus oxychloride is stirred, and one drop (catalyst) of N,N-dimethylformamide is added. The reaction mixture is then stirred at ambient temperature for about five hours, and then allowed to stand for about 72 hours. After this time, the reaction mixture is poured into 1000 mL of ice containing about one mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration and washed with water. The solid is then dried under reduced pressure at about 60° C. An NMR spectrum of the solid indicates that it contains a large amount of starting material. The solid is then dissolved in 25 mL of phosphorus oxychloride, and two drops of N,N-dimethylformamide are added. The mixture is heated to reflux where it is stirred for about 18 hours. After this time, the reaction mixture is poured into 600 mL of ice containing about two mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration, washed with water, and dried under reduced pressure at about 60 ° C., yielding 8.6 grams of 5-bromo-2-chloro-3-cyano-4,6-dimethylpyridine. The NMR spectrum is consistent with the proposed structure.