Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH:8](Br)[CH3:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[Br:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH:8]([N:32]2[CH2:31][CH2:30][N:29]([S:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)(=[O:28])=[O:27])[CH2:34][CH2:33]2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: CC(Br)c1ncc(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(=O)[nH]3)CC2)cc1
Yield: 53.4 %

Procedure:
In a round bottom flask containing 5-bromo-2-(1-bromo-ethyl)-3H-pyrimidin-4-one (1.0 g, 3.5 mmol) in acetonitrile (30 ml) was added KI (0.9 g, 5.3 mmol), K2CO3 (1.2 g, 5.3 mmol), and (1-(4-Methoxy-benzenesulfonyl)-piperazine (983 mg, 3.5 mmol). The reaction was heated at reflux for 12 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (15 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue purified by column chromatography (ethyl acetate: hexanes 1:1) to give 5-bromo-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-pyrimidin-4-one (Yield 854 mg, 53%). 1H NMR (400 MHz, CDCl3): δ 1.28 (d, J=7.0 Hz, 3H), 2.62-2.49 (m, 4H), 3.00-2.94 (m, 4H), 3.84 (s, 3H), 4.05 (q, 1H, J=7.0 Hz), 6.97 (d, J=11.8 Hz, 2H), 7.62 (d, J=11.8 Hz, 2H), 8.11 (s, 1H). MS m/z calc. 457.3, found (ESI); 457.2 (M+1)+. Retention time 2.50 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=C(C)O[N:33]=3)=[CH:28][CH:27]=2)[C:13]2[NH:14][C:15](=[O:24])[N:16]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].O.[C:39]([OH:42])(=[O:41])[CH3:40]>CO.[Fe]>[C:39]([OH:42])(=[O:41])[CH3:40].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH2:36])=[NH:33])=[CH:30][CH:31]=2)[C:13]2[NH:14][C:15](=[O:24])[N:16]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:23]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 70 mg of 5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 3 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 70 mg of iron powder, and the mixture was stirred at 60° C. for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid), to give 41 mg of the title compound.
Reaction SMILES: [CH2:1]([N:17]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.CN([CH:35]=[O:36])C>>[CH:35]([C:24]1[S:23][C:22]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18](=[O:21])[CH2:19][CH3:20])=[CH:26][CH:25]=1)=[O:36]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCCCCCN(C(=O)CC)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
75 g of N-hexadecyl-N-(2-thienyl)-propionic acid amide are dissolved in 59 cc. of anhydrous DMF and 36.7 g of phosphorus oxychloride are added thereto dropwise with ice cooling such that the temperature of the reaction mixture does not increase above 20° C. Stirring is continued for 1 hour and 20° C. and the reaction mixture finally is heated 3 hours to 80° C. Ice is added to the reaction mixture and 5 N soda lye is added until reaching a pH of 6. The resulting mixture is extracted with ether, the ethereal layer is separated, washed with water and dried over Na2SO4. The desired final product crystallizes at low temperature from the ethereal solution.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[O:17][CH2:16]1)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]([CH2:14][C@@H:15]2[CH2:16][O:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(C[C@@H]2CO2)c(Cl)n1
Yield: 105.1 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1 g, 6.78 mmol) and (R)-(−)-glycidyl tosylate (1.7 g, 7.45 mmol) were dissolved in tetrahydrofuran (THF) (10 ml), sodium hydrogencarbonate (600 mg, 7.14 mmol) was added to the solution, and the resulting mixture was stirred under reflux for 11 hours. The reaction mixture was concentrated under reduced pressure, water was added to the solution, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution in this order, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford (R)-2-chloro-4-nitro-1-(oxiran-2-ylmethyl)imidazole (1.45 g, yield 57%) as a light yellow oil.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])=[N-:2].[NH:12]1[C:19](=[O:20])[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].[OH-].[K+]>O>[N:2]([CH:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[NH:12][C:19]1=[O:20])=[N:1][CH:3]1[C:4](=[O:11])[NH:5][C:6](=[O:10])[NH:7][C:8]1=[O:9]
Reactant: [N-]=[N+]=C1C(=O)NC(=O)NC1=O
Reactant: O=C1CC(=O)NC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1NC(=O)C(N=NC2C(=O)NC(=O)NC2=O)C(=O)N1
Reaction time: 1.5 h

Procedure:
Introduced into 1100 g of distilled water at 85° C. were 46.2 g of diazobarbituric acid and 38.4 g of barbituric acid. The pH was then adjusted to about pH 5 using aqueous potassium hydroxide solution, followed by 90 minutes of stirring.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Na+].[Na+].[Cl-:21].Cl>O>[Cl-:21].[C:3]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH+:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][CH:9]=1)([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(CN2CCOCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C[NH+]2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 200 mL round-bottom flask was charged with 4-morpholin-4-ylmethyl-benzoic acid methyl ester (4.0 g, 0.017 mol, 1.0 eq). A solution of NaOH (2.0 g, 0.051 mol, 3.0 eq) in water was added and the reaction mixture was stirred overnight at room temperature. NaCl (5.0 g) and HCl (6.0 M in water, 17 mL, 6.0 eq) were then added. The reaction mixture was cooled to 0° C. and then stirred for 1 hr. The solid was collected by filtration, washed with pentane and dried at 50° C. under vacuum to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)=[O:19])[CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:44]1[N:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>O1CCOCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([C:44]2[C:45]([C:46]#[N:47])=[CH:48][CH:49]=[CH:50][N:51]=2)=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C(=O)NC4CC4)nn3-c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1ccc(Cl)c(C(=O)Nc2cc(C(=O)NC3CC3)nn2-c2ccccc2)c1

Procedure:
The title compound was prepared according to the method described for Example 83 using 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-N-cyclopropyl-1-phenyl-1H-pyrazole-3-carboxamide in dioxane (Preparation 10) and 2-chloronicotinonitrile with potassium carbonate as base.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[S:18].[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>N1CCCCC1>[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:6]2[C:5](=[S:18])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[O:8][CH:7]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: Cc1ccc2c(c1)C(=S)CC(c1ccccc1)O2
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc(C=C2C(=S)c3cc(C)ccc3OC2c2ccccc2)cc1

Procedure:
A solid mixture of 10 g 6-methyl-thioflavanone, 13 g 4-acetylaminobenzaldehyde and 8 drops piperidine is heated at 150°-160° C. for 3 hours. After allowing to cool, the crude brown glass is crystallized from ethanol. Pure 3-(4-acetylaminobenzylidene)-6-methyl-thioflavanone is obtained as a yellow solid; m.p. 197°-198° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:28][NH:29][S:30]([CH2:33][CH2:34][CH2:35]Cl)(=[O:32])=[O:31])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:7])[CH2:2][CH2:3][CH3:4].C(SCC(OC)CNS(CCC[I:64])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:28][NH:29][S:30]([CH2:33][CH2:34][CH2:35][I:64])(=[O:32])=[O:31])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane IIIe4 is allowed to react and worked up by the same procedure as described in (5). m.p. 82°-83° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4)CC3)c(OC)nc2c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.27 (s, 4H), 3.76 (s, 4H), 3.89 (s, 3H), 4.12 (s, 3H), 6.87-6.96 (m, 3H), 7.13 (s, 2H), 7.29-7.31 (m, 2H), 7.72-7.75 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[O:10]=[C:9]1[C:5]2=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:2](=[O:1])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Solvent: CN(C)C=O
Product: O=C1C2=C(c3ccccc3)N(Cc3ccccc3)C(=O)C2=C(c2ccccc2)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5.6 parts of potassium t-butylate are added to a suspension of 5.8 parts of 1,4-diketo-3,6-diphenylpyrrolo-[3,4-c]-pyrrole in 70 parts of dimethylformamide at 20° C. and the mixture is stirred at 20° C. for 1 hour. 7.6 parts of benzyl chloride are then added to the mixture and the mixture is kept at 65° C. for 2 hours. After cooling to 20° C., the reaction product is filtered off and washed with a little dimethylformamide and then with acetone and hot water. After drying, 4.5 parts of 1,4-diketo-2,5-dibenzyl-3,6-diphenylpyrrolo-[3,4-c]-pyrrole (formula XVII) are obtained and, if necessary, can be crystallised from dimethylformamide. Yellow-orange crystals of melting point 290°-292° C. are formed. ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([C@@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][NH2:29]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)([OH:9])[CH2:13][CH2:12][CH2:11][C:10]([NH:29][CH3:28])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@]2(c3cccc(Cl)c3)CCCC(=O)O2)C1
Solvent: CO
Product: CNC(=O)CCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 93 %

Procedure:
(R)-tert-butyl 3-((S)-2-(3-chlorophenyl)-6-oxotetrahydro-2H-pyran-2-yl)piperidine-1-carboxylate (60 mg, 0.153 mmol) was dissolved in a ca 30% solution of methylamine in methanol (3 mL). The mixture was stirred at it for 2 h then concentrated under reduced pressure to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-(methylamino)-5-oxopentyl)piperidine-1-carboxylate (60 mg, 93%), which was used directly without purification. 1H NMR (400 MHz, CDCl3): 1.12-1.45 (m, 3H), 1.46 (s, 9H), 1.58-1.81 (m, 6H), 2.05-2.17 (m, 2H), 2.50-2.58 (m, 2H), 2.69 (m, 3H), 4.06 (m, 1H), 4.12-4.28 (m, 2H), 7.22-7.32 (m, 3H), 7.43 (s, 1H). MS (E/Z): 425 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:23][C:24]([C:37]2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=CC=2OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:43](O)=[O:44]>C(Cl)Cl>[CH3:43][O:44][C:17]1[CH:18]=[CH:19][CH:14]=[CH:13][C:12]=1[CH2:11][N:10]1[CH2:9][CH:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:23]=[C:24]1[CH3:37]
Reactant: COc1ccccc1CCC(=O)NCC(Cc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CO
Solvent: ClCCl
Product: COc1ccccc1CN1CC(Cc2ccccc2)N=C1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The intermediate 1-phenyl-2-(tritylamino)-3-[N-(2-methoxybenzyl)acetylamino]propane (8.0 g, 14.4 mmol), prepared as described in Preparation 3, supra, was dissolved in 250 ml of methylene chloride and then cooled to 0° C. under a nitrogen atmosphere. Formic acid (5.5 ml, 144.0 mmol) was then added to the reaction solution and the resulting mixture was then warmed to room temperature. The reaction mixture was then stirred for about 2.5 hours. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH3:26])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>ClCCl>[NH2:24][C:19]1[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:16]2[CH:15]=[C:14]([CH:25]([N:27]3[CH2:28][CH2:29][N:30]([C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:31][CH2:32]3)[CH3:26])[CH:13]=[N:12][C:11]=2[NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[N:18]=1
Reactant: COc1ncc(Nc2ncc(C(C)N3CCNCC3)cc2-c2nc(C)nc(N)n2)cc1F
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(Nc2ncc(C(C)N3CCN(C(=O)N(C)C)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
A mixture of 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.141 g, 0.321 mmol) in dichloromethane (5 mL) was chilled to 0° C. in an ice bath, then triethylamine (0.224 mL, 1.604 mmol) was added to the mixture while stirring. After 10 min, dimethylcarbamic chloride (Aldrich; 0.104 g, 0.962 mmol) was added into the mixture slowly via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (25 g) eluting with a 20% mixture of 10:1 methanol/ammonium hydroxide in dichloromethane to give 4-(1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-N,N-dimethylpiperazine-1-carboxamide (0.070 g, 0.137 mmol, 42.7% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.34 (s, 1H) 9.40 (d, J=2.15 Hz, 1H) 8.17-8.23 (dd, 1H) 8.12 (d, J=2.54 Hz, 1H) 8.09 (d, J=2.15 Hz, 1H) 4.04 (s, 3H) 3.10-3.98 (m, 9H) 2.85 (s, 6H) 2.56 (s, 3H) 1.88 (d, J=6.85 Hz, 3H). m/z (ESI, +ve ion) 533 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].C(O)C.[C:12](=S)=[S:13]>>[SH:13][C:12]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: S=C=S
Solvent: CCO
Product: Sc1nc2cnccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 25 g (0.23 mol) of 3,4-diaminopyridine in 750 mL of ethanol containing 50 mL (63.2 g, 0.83 mol) of carbon disulfide was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and the beige precipitate which had formed was collected by filtration and allowed to air dry overnight. The product amounted to 33.5 g, m.p. >320° C.
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][O:10]CCO[Si](C)(C)C)[C:7](=[O:18])[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:4][N:3]1[CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:27]>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:8](=[CH:9][OH:10])[C:7](=[O:18])[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]1[CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:27]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COCCO[Si](C)(C)C)C2=O)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=CO)C2=O)C(C)C)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
2-[2,4-Dioxo-5-phenyl-3-[2-(trimethylsilyloxy)-1-ethoxymethylene]-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (12q) was combined with trifluoroacetic acid (10 mL) under argon and cooled to 0-5° C. After approximately 20 min., the reaction mixture was evaporated in vacuo. The residue was triturated with diethyl ether and hexane, filtered and dried under high vacuum to provide 2-[2,4-dioxo-3-(hydroxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (12r, 0.927 g) as a solid. 1H NMR (400 MHz, CDCl3) 0.91 (d, J=2, 3H), 0.92 (d, J=2, 3H), 3.63 (m, 1H), 3.80 (s, 3H), 3.81 (d, J=17 Hz, 1H), 3.96 (d, J=17 Hz, 1H), 4.17 (dd, J=7, 12 Hz, 1H), 4.29 (dd, J=7, 12 Hz; 1H), 4.92 (m, 1H), 5.89 (d, J=6 Hz, 1H), 5.95 (d, J=6 Hz, 1H), 6.92 (m, 2H), 7.09 (m, 2H), 7.27 (m, 3H), 7.37 (m, 2H). MS (ESI) [M+Na]+=460
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:20][C@H:10]2[CH2:11][CH2:12][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NC1CCCCC1
Product: c1ccc([C@H]2CC[C@H](NC3CCCCC3)CC2)cc1

Procedure:
from 4-phenylcyclohexanone and cyclohexylamine. Melting point: 68°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.O.NN.[OH-].[Na+].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][NH2:15])[O:10][CH2:11][CH2:12][O:13]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C2(CN)OCCO2)cc1
Temperature: 25 °C

Procedure:
2-[2-(4-Methoxyphenyl)-[1,3]dioxolan-2-ylmethyl]isoindole-1,3-dione (Preparation 41, 2.0 g, 5.90 mmol) and hydrazine hydrate (5 mL) were combined. The stirred reaction mixture was heated under reflux for 48 h then allowed to cool to rt. Aqueous sodium hydroxide (2M, 10-15 mL) and water (20 mL) were added and the mixture stirred until a solution was formed. Diethyl ether (20 mL) was added and the biphasic mixture stirred vigorously for 16 h. The layers were separated and the aqueous layer was extracted with diethyl ether (3×20 mL), then the combined organic extracts were washed with brine (20 mL). The ethereal solution was passed through a filter paper then evaporated to dryness in vacuo to give the title compound as a yellow oil, which solidified on standing. δH (CDCl3): 1.42 (2H, br s), 3.06 (2H, s), 3.97 (3H, s), 4.00 (2H, t), 4.21 (2H, t), 7.04 (2H, d), 7.53 (2H, d).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])C=C[C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]([O:17][CH3:18])(C)[CH3:15]>CCOCC.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:13][CH:14]([O:17][CH3:18])[C:15]1[CH:4]=[CH:3][C:2]([F:1])=[C:9]([F:10])[C:8]=1[F:11]
Reactant: O=Cc1ccc(F)c(F)c1F
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(OC)c1ccc(F)c(F)c1F
Yield: 71.7 %

Procedure:
A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue wasdistilled under high vacuum to give the title compound (23.07 g, 71.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.[ClH:46]>>[ClH:46].[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=C3C(=O)Nc4ccccc43)ccc21
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1Nc2ccccc2C1=Cc1ccc2[nH]nc(/C=C/c3ccncc3)c2c1

Procedure:
According to the method of A57C and D, 3-((3-((E)-2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)methylene)indolin-2-one (13.1 mg, 0.026 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl (water/EtOH) treatment. Suction filtration gave a solid which was rinsed with 1:1 EtOH:water (2×1 mL). Pumping under high vacuum gave an orange solid (7.3 mg, 69%, 55:45 mixture of E/Z isomers, HCl salt). 1H NMR (400 MHz, CD3OD) δ 9.83 (s, 0.4H), 8.73 (m, 2H), 8.59 (s, 0.6H), 8.33-8.20 (m, 3.5H), 7.95 (m, 1H), 7.91-7.87 (m, 1H), 7.80-7.63 (m, 3H), 7.25 (t, J=8.4 Hz, 1H), 7.07 (t, J=7.6 Hz, 0.4H), 6.96-6.87 (m, 1.6H); MS ESI 365.2 [M+H]+, calcd for [C23H16N4O+H]+ 365.14.