Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ncc(-c3ccc(OC)cc3)n2c1
Yield: 55.9 %

Procedure:
A mixture of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate (1.40 g, 4.63 mmol), (4-methoxyphenyl)boronic acid (845 mg, 5.56 mmol), tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.232 mmol), 2 M aqueous sodium carbonate solution (4.63 mL) and 1,2-dimethoxyethane (50 mL) was heated under reflux under an argon atmosphere overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to give the title compound (730 mg, yield 56%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][NH:4][C:3]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18].C([O-])(O)=O.[Na+]>C(OCC)C.C(Cl)Cl.CCCCC>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([C:5]1[NH:4][C:3]([CH3:8])=[C:2]([F:1])[C:6]=1[F:7])=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1[nH]cc(F)c1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,4-Difluoro-2-methyl-1H-pyrrole (Intermediate 8; 3.8 g) was dissolved in anhydrous diethyl ether (100 ml). Anhydrous K2CO3 (12.5 g) was added followed by trichloroacetyl chloride (10 ml). The mixture was stirred at room temperature under N2 for 2 h, poured into a cold saturated solution of NaHCO3, stirred for 10 min, and extracted with ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a red brown oil. Trituration with pentane (50 ml)/DCM (2 ml), at −20° C. overnight to gave the title compound as a brown powder (1.3 g). MS (ES) MH+: 262 for C7H4Cl3F2NO; NMR (CDCl3): 2.35 (d, 3H), 9.0 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: CC(=O)N(C)C
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.13 g (0.0005 mole) of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.135 g of 2-chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-10) as an yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:21]=O)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:31])([OH:30])[OH:29].[BH3-]C#N.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:21][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:29])([OH:31])[OH:30])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(C=O)nc2-c2ccccc2)cc1
Reactant: NCCCCP(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(-c2ccc(CNCCCCP(=O)(O)O)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure M, 5-(4-ethyl-phenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 56, 58 mg, 0.18 mmol), 4-aminobutylphosphonic acid (21 mg, 0.18 mmol), Bu4NOH (0.18 ml, 0.18 mmol, 1 M in MeOH) and NaCNBH3 (9 mg, 0.18 mmol) in MeOH (2 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (5 g, 26.7 mmol), 2-(trifluoromethyl)phenol (4.8 h, 29.4 mmol) and triphenylphosphine (8.4 g, 32 mmol) in THF (75 mL) at rt was added DEAD (5.1 mL, 32 mmol) over 5-10 min. The mixture was stirred at rt for 2 days. Solvent was evaporated. The residue was diluted with EtOAc and washed successively with 1 N aqueous NaOH and brine. The EtOAc layer was separated, dried (Na2SO4) and concentrated. Chromatography over silica gel and elution with hexanes/EtOAc (10:1, then 3:1) gave tert-butyl (3R)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate as a colorless oil, which solidified on standing. 1H NMR (500 MHz, acetone-d6): δ 7.63 (m, 2 H), 7.31 (d, 1 H), 7.13 (t, 1 H), 5.26 (s, 1 H), 3.68-3.43 (m, 4 H), 2.21 (m, 2 H), 1.45 (s, 9 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[F:24][C:23]([F:26])([F:25])[C:22]1[C:17]([O:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: OCc1ccnc2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cccnc1OCc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxymethyl-7-chloroquinoline (0.6 g, 3.12 mmol) was dissolved with stirring in dry THF (20 mls) and sodium hydride (0.15 g, 60% dispersion in mineral oil, 3.75 mmol) added. The mixture was stirred at room temperature for one hour and 2-chloro-3-trifluoromethylpyridine (0.62 g, 3.42 mmol) added. The mixture was stirred overnight and worked up to provide the product (0.9 g, % as a tan solid, mp 125-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33](SC)[NH:34][CH:35]=2)=[CH:25][CH:24]=1>C(O)C>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33]([NH:15][CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[C:3]([C:18]([F:19])([F:20])[F:21])[CH:4]=4)=[CH:8][CH:9]=3)[NH:34][CH:35]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2ccc(Cl)nc2)c[nH]1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1ccc(Cl)nc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1.0 eq) and 5-(6-chloro-pyridin-3-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.190 mmol, 0.6 eq) were dissolved in dry ethanol (300 μL) and stirred at 130° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-7% in 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(6-chloro-pyridin-3-ylmethyl)-2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (0.084 mmol, yield: 26%, HPLC-MS/UV:[M+H]+=536.33; rt: 1.24 mins; purity: 95%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.89 (t, J=7.17, 2H), 3.57 (s, 2H), 3.59-3.66 (m, 2H), 5.23 (br.s., 1H), 6.95 (dd, J=8.51, J=9.86, 2H), 7.03 (dd, J=9.41 J=2.24, 1H), 7.17-7.23 (m, 3H), 7.27-7.30 (m, 2H), 7.39 (dd, J=9.07, J=8.31, 1H), 7.47 (dd, J=8.06, J=2.51, 1H), 7.65 (s, 1H), 8.28 (d, J=2.26, 1H), 12.01 (br.s., 1H)
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:13][CH:12]=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]=1[C:37](=[O:39])[CH3:38])C1C=CC=CC=1.FC(F)(F)C(O)=O.O.CSC>ClCCl>[CH2:30]([O:29][C:11]1[C:10]([C:37](=[O:39])[CH3:38])=[C:9]([OH:8])[C:14]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:13][CH:12]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 1-[2,6-bisbenzyloxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (10.6 g) in dichloromethane (15 mL) was added a mixed solvent of trifluoroacetic acid/water/dimethylsulfide (7/3/1) (30 mL), and the mixture was stirred at room temperature for 12 hours. Adding water, the reaction mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate until the aqueous layer became weak alkaline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (8.07 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:28][C@H:29]2[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30]2)[CH:22]=[CH:21]3)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[C@H:29]1([NH:28][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:16])[CH:19]=3)[N:24]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.040 mmol) was dissolved in methylene chloride (1.0 mL). At 0° C. trifluoroacetic acid (0.030 mL, 0.40 mmol) was added and the reaction mixture was stirred at ambient temperature over night. 20% sodium carbonate solution in water was added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried on magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography (silica gel, methylene chloride:methanol gradient=95:5→2:1) to yield the title compound (5.0 mg; 31%) as an off-white solid; MS: m/e=402.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>O1CCCC1>[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:26])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reactant: Cc1cc(N)cc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C)cc(C(=O)O)c1
Yield: 51.8 %

Procedure:
3-Amino-5-methylbenzoic acid (1.9 g) is dissolved in a 60% aqueous solution of tetrahydrofuran (30 ml) containing triethylamine (2.3 g), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenyl-propionyl chloride (3.2 g) in tetrahydrofuran (20 ml) with stirring under ice cooling, and the mixture is stirred at room temperature for 2 hours. Tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then ethyl acetate is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][C:26]=1[O:27][CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[N:25][C:26]([O:27][CH3:28])=[C:21]([F:20])[CH:22]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ncc(B(O)O)cc1F
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ncc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)cc1F
Yield: 59.5 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (175 mg, 0.48 mmol) and 5-fluoro-6-methoxypyridine-3-boronic acid (162 mg, 0.96 mmol) were reacted. After purification the title compound (106 mg, 61% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bm, 1H), 8.15 (m, 1H), 7.92 (a dd, J=5.2, 9.0 Hz, 1H), 7.65 (a d, J=10.7 Hz, 1H), 7.56 (a t, J=9.0 Hz, 1H), 4.10(s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=372, HPLC 2.59 min.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.Cl[CH2:42][CH2:43][S:44][CH3:45].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CC#N>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:42][CH2:43][S:44][CH3:45])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: CSCCCl
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CSCCN1CCC(N2Cc3cc4nc(-c5c(NCC(O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 100 °C

Procedure:
A mixture of the 2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (542 mg, 1.0 mmol), 1-chloro-2-methylsulfanyl-ethane (122 mg, 1.1 mmol), Na2CO3 (318 mg, 3.0 mmol) and NaI (150 mg, 1.0 mmol) in CH3CN (20 mL) was heated at 100° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (200:10:1) afforded the title compound. 1H NMR (DMSO-d6) δ 1.69-1.82 (4H), 2.09 (s, 3H, CH3), 2.09 (m, 2H), 2.19 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.50-2.59 (4H), 3.00 (m, 2H), 3.38 (m, 2H), 3.53 (m, 1H), 3.70 (m, 1H), 3.98-4.08 (3H), 4.15 (m, 1H), 4.43 (s, 1H), 4.47 (s, 1H), 5.47 (br s, 0.5H, NH), 5.53 (br s, 0.5H, NH), 6.20 (m, 1H), 6.80-6.99 (3H), 7.30-7.36 (1.5H), 7.68 (s, 0.5H), 7.79 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (br d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 617.5 (MH+).
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: BrCc1cccc(Br)c1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: Nc1nc(N)c2nc(CN3CCN(Cc4cccc(Br)c4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added m-bromobenzyl bromide (34 mg; 0.14 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 15 mg of yellow colored 3-[4-(3-Bromo-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Cl
Yield: 87.8 %

Procedure:
A mixture of 7-chloro-2-iodo-thieno[3,2-b]pyridine-6-carbonitrile (1.00 g, 3.12 mmol), 4-formylphenylboronic acid (936 mg, 6.24 mmol) and 108 mgs of tetrakis(triphenylphosphine)palladium (0) in 30 mL of ethylene glycol dimethyl ether and 25 mL of aqueous saturated sodium bicarbonate is heated at reflux for 4 hours. The mixture is cooled and the precipitate is collected by filtration washing with ethyl acetate and diethyl ether to provide 818 mg of 7-chloro-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 300–305° C.; 1H NMR (CDCl3) δ 7.93 (d, J=8 Hz, 2H), 7.96 (s, 1H), 8.03 (d, J=8 Hz, 2H), 8.87 (s, 1H), 10.1 (s, 1H), MS 298.0, 300.0 (M−H)−H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10](O)[CH3:11])([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.CS([Cl:26])(=O)=O>CN(C)C=O>[Cl:26][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
311 g 1-(2-nitrophenyl)ethanol (XI-1) (95.8% purity, 1.78 mol) are dissolved in 3000 ml dimethyl formamide in a 6 liter three-necked flask equipped with a stirrer, dropping funnel and thermometer. 921.4 g (7.13 mol) diisopropylethylamine are added in a single portion, stirred for 5 minutes, then 612.5 g (5.35 mol) methanesulfonyl chloride are added dropwise between 20 to 35° C. with good cooling. After the reaction has subsided, it is stirred for another 90 hours at room temperature, and the solvent is removed under vacuum. Then the residue dissolved in ethyl acetate, washed 3 times with water, dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified by column chromatography (silica gel, 9:1 hexane/acetone). 219 g of 1-(1-chloroethyl)-2-nitrobenzene (100% purity by HPLC, 66.2% theoretical yield) are obtained as a brown oil [logP (pH 2.3)=2.87].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10].[OH-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccccc1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccccn1
Yield: 89.2 %

Procedure:
A mixture of 3.0 g of methyl 2-(2-pyridinyl)benzoate and 600 mg of sodium hydroxide in 50 ml of 9:1 methanol:water is refluxed for 4 hours. The reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml of cold water. The solution is neutralized with glacial acetic acid and the resulting product filtered, washed with water, and dried to give 2.5 g of the desired product:M+=200.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:21]1[N:22]=[N:23][C:24]([CH3:27])=[CH:25][N:26]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]([OH:34])[CH2:27][C:24]2[N:23]=[N:22][C:21]([C:15]3[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=3[F:20])=[N:26][CH:25]=2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cnc(-c2c(F)cccc2F)nn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(Cc1cnc(-c2c(F)cccc2F)nn1)c1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
At −20° C., 1.5 ml of n-butyllithium (1.6M in hexane) are added to 202 mg of diisopropylamine in 6 ml of tetrahydrofuran. After 15 min. the reaction mixture is cooled to −50° C. and 0.414 g of 3-(2,6-difluorophenyl)-6-methyl-[1,2,4]triazine in 2 ml of tetrahydrofuran is added dropwise. After 20 min. the mixture is cooled to −70° C., 0.281 g of 4-chlorobenzaldehyde in 3 ml of tetrahydrofuran is added dropwise and the mixture is then stirred at −70° C. for 2 h. The reaction mixture is then poured into ice-water and extracted with ethyl acetate; the organic phase is concentrated and the residue is purified by means of flash chromatography. In this way 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol is obtained in the form of a light-brown resin. After recrystallisation from diethyl ether/hexane, 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol is obtained in the form of beige crystals having a melting point of 98-102° C.