Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(N[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])C=CC=CC=1.[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([OH:40])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]>CO>[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([O:40][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(O)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 40 h
Yield: 36 %

Procedure:
To a solution in 2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 18, (0.312 g, 1.23 mmol) in MeOH (10 mL) containing diisopropylethylamine (0.214 mL, 1.23 mmol) at 0° C. under N2 is added N-phenyltrifluoromethanesulfonamide (0.439 g, 1.23 mmol). The reaction is warmed slowly to room temperature and stirred for 40 hours. The solvent is removed under reduced pressure and the crude oil which remains is purified over silica (EtOAc:heptane 1:9) to afford 0.170 g (36% yield) of the desired compound as a yellow oil. 1H NMR (250 MHz, MeOD) δ ppm 8.85 (1H, br s), 8.19 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=2.3 Hz), 3.74 (3H, s), 1.63 (6H, s). HPLC-MS: m/z 387 [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[CH:24][NH:23][C:22]=1[NH2:26])=[O:20])[CH3:17].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br-:15].[NH2:26][C:22]1[NH:23][C:24]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N+:9]=2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:25][C:21]=1[C:19]([O:18][CH2:16][CH3:17])=[O:20]
Reactant: CCOC(=O)c1cc[nH]c1N
Reactant: Brc1cccc[n+]1Cc1ccccc1
Agent: [Br-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cccc[n+]2Cc2ccccc2)[nH]c1N
Reaction time: 48 h

Procedure:
Under an argon atmosphere, 658 mg (2.0 mmol) of N-benzyl-2-bromo-pyridinium bromide (for preparation see: J. Heterocyclic Chem. 28, 1083 (1991)) are introduced into 20 ml of abs. methylene chloride, and 308 mg (2.0 mmol) of 2-amino-pyrrole-3-carboxylic acid ethyl ester [for preparation see: J. Heterocyclic Chem. 23, 1555 (1986)] are added thereto. The reaction mixture is stirred for 2 days with the exclusion of light. Since the reaction is not complete, 232 μl (2 mmol) of 2,6-lutidine and a further 0.20 mmol of 2-amino-pyrrole-3-carboxylic acid ethyl ester are added. After a further 12 hours' stirring, the reaction mixture is concentrated by evaporation and the residue is digested in isopropanol. Filtering, washing with hexane and drying yield the title compound which, according to its 1H-NMR spectrum, still contains approximately 10% N-benzyl-2-bromo-pyridinium bromide; 1H-NMR (300 MHz, DMSO-d6): 11.45 (1H), 8.70 (d, J=7, 1H), 8.38 (t, J=7, 1H), 8.00 (d, J=7, 1H), 7.67 (t, J=7, 1H), 7.42 (m, 3H), 7.14 (d, J=7, 2H), 6.85 (d, J=3, 1H), 6.45 (sb, 2H), 5.91 (s, 2H), 4.13 (q, J=7, 2H), 1.19 (t, J=7, 3H); FAB-MS: (M+H)+ =322.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCNCC2)C3)CC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.91 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH3:11].P(Br)(Br)[Br:14]>>[Br:14][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH3:11]
Reactant: CCC(O)c1cccc(F)c1F
Reactant: BrP(Br)Br
Product: CCC(Br)c1cccc(F)c1F

Procedure:
rac-1-(1-Bromo-propyl)-2,3-difluoro-benzene was prepared from rac-1-(2,3-Difluoro-phenyl)-propan-1-ol and phosphorus tribromide in analogy to Example 23 b): colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([C@@H:14]2[CH2:18][N:17]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=3)[C@H:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:25][CH2:26]3)=[O:20])[CH2:15]2)[N:13]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1ccc(F)cc1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccc(F)cc2)CC1
Yield: 11 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 4-fluoro-benzaldehyde (17 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (8.2 mg, 11%) as light yellow oil. MS m/e=573.1 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[C:9](OCC)=[O:10]>CCOCC>[CH3:7][C:8]([CH3:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:9][OH:10]
Reactant: C=CCCC(C)(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCC(C)(C)CO
Temperature: 22 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
To a stirred solution of 1M LAH in ether (142.14 mL, 142.14 mmol), at 0° C. and under nitrogen, was added dropwise ethyl 2,2-dimethylhex-5-enoate (11.00 g, 64.61 mmol) dissolved in 100 mL anhydrous ether over 1 hour. This reaction solution was stirred at 22° C. for 20 hours, then quenched with water (3 mL), 1M NaOH (11 mL) and water (9 mL), dried over Na2SO4, filtered and concentrated to give the title product (7.22 g, 87.09%). 1H NMR (500 MHz, CDCl3) δ 5.85-5.77 (m, 1H); 5.01 (d, 1H); 4.93 (d, 1H); 3.33 (d, 2H); 2.03 (m, 2H); 1.34 (m, 2H); 0.89 (m, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([NH:13]C(=NC)SC)#[N:12]>>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:11]([NH2:13])=[NH:12]
Reactant: CN=C(NC#N)SC
Reactant: NCCSCc1nccs1
Product: N=C(N)NCCSCc1nccs1

Procedure:
Reaction of [(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide 20.2 g) with N-cyano-N',S-dimethylisothiourea (7.75 g) by a procedure similar to that described in Example 75, afforded N-cyano-N'-methyl-N"-[(2-(2-thiazolylmethylthio)ethyl]guanidine, m.p. 120°-122.5°, following chromatography on silica gel with alcohol.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:14]>C(O)(=O)C>[CH2:1]([CH:8]([CH2:12][Br:14])[CH2:9][C:10]([OH:11])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: O=C1CC(Cc2ccccc2)CO1
Solvent: CC(=O)O
Product: O=C(O)CC(CBr)Cc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 4-benzyl-dihydrofuran-2-one (1.0 g, 5.6 mmol), acetic acid (1.7 mL), HBr (33% in acetic acid, 2.0 mL) is heated at 80° C. for 4 h. The mixture is cooled to room temperature, poured into ice-water (20 mL), and extracted with chloroform (2×30 mL). The combined organic extracts are washed with water and brine, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 3-benzyl-4-bromo-butyric acid, 1.5 g (99%), as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22]I>>[CH3:22][N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CI
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(N=c2sc3ncccc3c(=O)n2C)cc1
Yield: 70 %

Procedure:
The reaction procedure of Example 11 was followed except that 949 mg (3.52 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 28 mg of lithium hydride and 500 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 698 mg of 2,3-dihydro-3-methyl-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (70%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([N:19]([CH3:41])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1
Reactant: CI
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(F)(F)F)cc1)C(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-(4-(trifluoromethyl) benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide Example 34) (22 mg, 0.041 mmol) in anhydrous DMF at room temperature was added sodium hydride (6.5 mg, 0.164 mmol). The resulting suspension was stirred at room temperature for 5 min, then iodomethane (25 μL, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (30 mL), washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluting with a gradient of EtOAc (0-60%) in hexanes to afford 15 mg (66%) of the title compound as a white powder. HPLC/MS (method A): retention time=3.85 min, (M+H)+=556.3
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[N:10]([O-])=[O:11].[Na+].CC(O)=O>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:10]=[O:11])=[C:4]([NH2:9])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(N)n1

Procedure:
The process according to claim 1 wherein 2,4,6-triaminopyrimidine is reacted with an equimolar amount of sodium nitrite in the presence of about 1.5 molar amount of HOAc in the presence of water to produce the intermediate 2,4,6-triamino-5-nitrosopyrimidine in the form of a stirrable slurry.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].IC.[C:16]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:16]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A mixture of 608 mg (2.4 mmol) of 2-bromo-4-trifluoromethoxyphenol, 0.35 mL (5.6 mmol) of iodomethane and 775 mg (5.6 mmol) of K2CO3 in 2 mL of DMF was stirred at rt for 2.5 h. The reaction mixture was partitioned between 100 mL of hexanes and 100 mL of H2O and the layers were separated. The organic layer was washed with 2×100 mL of H2O, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using hexanes as the eluant afforded 579 mg (89%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.91 (s, 3H), 6.88 (d, J=9.2, 1H), 7.15-7.18 (m, 1H), 7.45 (app d, J=3.2, 1H).
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(=O)C([Cl:15])=O>C1(C)C=CC=CC=1>[C:1]([Cl:15])(=[O:11])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 135.9 %

Procedure:
trans-Cinnamic acid (5 g, 33.7 mmol, Aldrich) was dissolved in toluene (100 mL), and the solution was cooled to 0° C. and flushed with N2. Anhydrous DMF (0.1 mL) was added, followed by oxalyl chloride (8.56 g, 5.88 mL, 67.4 mmol) dropwise over 8 minutes. The mixture was stirred at 0° C. for 1 hour and at room temperature for 1.5 hours. The solvent was removed under vacuum to give the title compound (7.63 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:17]([O:19]CC)=O.[CH2:22]([N:25]=[C:26]=[S:27])[CH:23]=[CH2:24].[OH-].[K+]>C(O)C.O>[CH2:22]([N:25]1[C:17](=[O:19])[C:3]2[C:4]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:1][C:26]1=[S:27])[CH:23]=[CH2:24]
Reactant: CCOC(=O)C1=C(N)c2ccccc2CC12CCCCC2
Reactant: C=CCN=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Temperature: 85 °C

Procedure:
Ethyl 4′-amino-1′H-spiro[cyclohexane-1,2′-naphthalene]-3′-carboxylate 18 (Scheme 8, 1.66 g, 5.82 mmol) and allyl isothiocyanate (0.600 ml, 6.13 mmol) were dissolved in Ethanol (9.69 ml) and refluxed at 85° C. for 10 h. A solution of potassium hydroxide (0.653 g, 11.63 mmol) in Water (9.69 ml) was then added and the reaction mixture was refluxed for 3 h. The cooled r×n mixture was acidified to pH 3.0-3.5. The precipitate was filtered off, washed with water and recrystallized from butanol.
Reaction SMILES: [OH:1][CH:2]([C:6]1[S:10][C:9]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH:15]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:8][CH:7]=1)[CH2:3][O:4][CH3:5].C([O-])(=O)C.[NH4+:37].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:5][O:4][CH2:3][CH:2]([C:6]1[S:10][C:9]([C:11]2[NH:37][C:14]([CH:15]([C:23]3[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=3)[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:7]=1)[OH:1]
Reactant: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(SC)cn2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(SC)cn3)[nH]2)s1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 1-[5-(1-hydroxy-2-methoxyethyl)-1,3-thiazol-2-yl]-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (103 mg) in acetic acid (1.7 mL) was added ammonium acetate (265 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (62.8 mg, yield 64%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1N
Product: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 29 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 4-chloro-3-trifluoromethylphenyl isocyanate, the title compound (15 mg, 29%) was obtained as a pale brown powder.
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: CCN1CCC(N)CC1
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 90.6 %

Procedure:
To a mixture of 1.1371 g (4.0 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.5129 g (4.0 mmole) of 4-amino-1-ethylpiperidine followed by 1.0119 g (10 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 65 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.0056 g 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:49]1[CH2:50][CH2:51][CH:46]([CH2:45][O:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:47][CH2:48]1)(=[O:18])[CH3:16]
Reactant: Clc1cnc2nc1Nc1ccc(OCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 66% yield. LCMS for C25H28ClN6O2 (M+H)+: m/z=479.1.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:8][C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(C(F)(F)F)cc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)nc(N)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-(trifluoromethyl)-4(3H)-pyrimidinone (250 mg, 1.4 mmol), triethylamine (196 μL, 1.4 mmol), N,N-dimethylaminopyridine (17 mg, 0.14 mmol), in CH2Cl2 (13 mL) cooled to 0° C. was added p-toluenesulfonyl chloride (534 mg, 2.8 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with CH2Cl2, washed with H2O (2×20 mL) followed by brine, dried (Na2SO4), evaporated, and dried under vacuum. Desired compound (466 mg, 1.4 mmol; 99+% yield; ES MS [M+H]+=140.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:11][CH2:12][CH2:13][O:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17].[NH3:24]>C(O)C>[CH2:19]([O:18][P:16]([CH2:15][O:14][CH2:13][CH2:12][O:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:24])([O:21][CH2:22][CH3:23])=[O:17])[CH3:20]
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)ncnc21)OCC
Reactant: N
Solvent: CCO
Product: CCOP(=O)(COCCOn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C

Procedure:
A solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]purine (1.45 g, 4 mmol) in ethanol (20 ml) saturated with ammonia gas was heated in a sealed steel vessel at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, evaporated to dryness and the residual oil chromatographed on silica gel (eluted with dichloromethane: methanol, 90:10) to give recovered starting material (0.25 g) and the title compound (0.94 g, 82%--based on used starting material), crystallised from acetone-ether, m.p. 74°-76°. UV: λmax (EtOH) 260 nm (ε 13,500); IR: νmax (KBr) 3308, 3146, 1669, 1646, 1600, 1538, 1466, 1416, 1320, 1301, 1232, 1206, 1164, 1129. 1066, 1053, 1039, 1009, 978 cm-1 ; 1H NMR: δH [(CD3)2SO]1.24 (6H,t,J=7 Hz, (OCH2CH3)2), 3.83-3.89 (2H,m,CH2OCH2P), 3.91 (2H,d,J=8 Hz, OCH2P), 4.0-4.15 (4H, dq, J=7 Hz, 7 Hz, (OCH2CH3)2), 4.48-4.51 (2H,m,N-OCH2), 7.37 (2H,br.s,D2O exchangeable NH2), 8.14 (1H,s,H-8), 8.34 (1H,s,H-2). Found: C,41.74; H: 5.49; N: 20.06%; m/z 345.1202. C12H20N5O5P requires: C,41.74; H, 5.83; N, 20.28%; m/z 345.1212.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3]1.[OH-].[K+].Br[CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CS(C)=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)=[CH:3]1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cn1cc(CN2CCNCC2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(CN2CCN(CCOc3ccc(C=O)cc3)CC2)c2ccccc21
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A suspension of 1-(1-methylindole-3-ylmethyl)piperazine (1.3 g) in dimethylsulfoxide (15 ml) and potassium hydroxide (0.63 g) was stirred for 30 min under nitrogen at 22° C. and then a solution of 4-[2-bromoethoxy]benzaldehyde (1.3 g) was added and stirring was continued for further 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed on silica gel using mixture of methanol: chloroform (1:9) as eluent to afford the pure product (0.76 g, 51%) as an oil.