Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:12][CH2:13][CH2:14][C:15]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:19][CH2:18][CH2:17][O:16]1)CC)[C:3]1C=CC=CC=1.Cl.CO.[H][H]>[Pd].CO>[ClH:1].[CH2:2]([NH:9][CH2:12][CH2:13][CH2:14][C:15]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:16][CH2:17][CH2:18][O:19]1)[CH3:3]
Reactant: [H][H]
Reactant: CCN(CCCC1(c2ccc(F)cc2)OCCO1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNCCCC1(c2ccc(F)cc2)OCCO1
Temperature: 25 °C
Yield: 96849.9 %

Procedure:
A suspension prepared from 47.2 g (0.124 mmol) of 2-[3-(N-benzyl-N-ethylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride, 0.035 ml of saturated HCl/methanol, 350 ml of methanol, and 4 g of 5% palladium on carbon was shaken at 50° under 50 psi hydrogen for 5 hours. The mixture was allowed to cool to room temperature and filtered. Evaporation of the solvent followed by trituration with ether provided 34.8 g (96%) of product. Recrystallization from ether/isopropyl alcohol provided analytically pure material.
Reaction SMILES: [Li+].CCC[CH2-].[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[O:12]1[CH2:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:6][C:7]1[S:8][C:9]([CH:15]([OH:12])[CH2:14][CH3:13])=[CH:10][CH:11]=1
Reactant: Cc1cccs1
Reactant: C1COC1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1ccc(C)s1
Reaction time: 2.25 h
Yield: 17.6 %

Procedure:
N-Butyllithium in hexane (1.5M; 35.6 ml) was added dropwise at room temperature under nitrogen to a solution of 2-methylthiophene (5.0 g) in dry THF (50 ml). After stirring for 2.25 h, oxetane (4.42 g) in dry THF (15 ml) was added dropwise and stirring continued for 22.5 h. Saturated ammonium chloride solution (200 ml) was added and the mixture extracted with diethyl ether (3×200 ml), dried and evaporated in vacuo to give an oil. Purification by FCC on silica gel with cyclohexane-diethyl ether (1:1) as eluent gave the title compound as a pale orange oil (1.4 g). T.l.c. (cyclohexane-diethyl ether 1:1) Rf 0.31.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[CH3:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH-].[Na+]>CN(C=O)C>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[C:14]([CH3:13])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Yield: 76.9 %

Procedure:
A solution of commercially available 3,4,5-trifluoro-nitrobenzene (25b) (5.0 mL, 42.8 mmol), diethyl methylmalonate (6.1 mL, 35.7 mmol), and sodium hydroxide (1.54 g, 38.5 mmol) in DMF (55 mL) was allowed to react in the same manner as in (a) in Production Example 1. The crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 9.1 g (63%) of compound (26b) of interest as clear brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(O)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCCl)cc1
Temperature: 40 °C
Yield: 47 %

Procedure:
A solution of 3-[(4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one (0.945 g, 3.75 mmol) in 20 mL DMF is treated with potassium carbonate (777 mg, 1.5 equiv.) and 1-bromo-4-chlorobutane (1.1 equiv.). The reaction mixture is heated to 40° C. for 3 h. The reaction mixture is partitioned between EtOAc and water. The organic layer is collected and washed sequentially with H2O (1 ×), saturated aqueous NaHCO3 solution (1 ×), and brine (1 ×). The organic phase is dried and concentrated to give a solid. The solid is triturated with MeOH and collected by filtration to give the named compound as yellow solid (600 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>CS(C)=O>[F:14][C:15]1[N:16]=[C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cc(C#N)ccc1O
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C#N)ccc1Oc1cccc(F)n1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17 mmol) in DMSO (15 mL) was added sodium hydride (0.44 g, 18 mmol) and 2,6-difluoropyridine (1.0 g, 8.7 mmol). After heating at 100° C. for 18 hours the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was removed in vacuo to give 4-(6-fluoropyridin-2-yl)oxy-3-methoxybenzonitrile (1.3 g); NMR (CDCl3) 7.8 (q,1), 7.35 (m,1), 7.25 (m,2), 6.85 (d,1), 6.65 (m,1), 3.85 (s,3) ppm.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:16][C:17]1[CH:23]=[CH:22]C(N)=[CH:19][C:18]=1[O:24][CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:16][C:17]1[CH:23]=[CH:22][C:1]([NH:2]/[C:3](/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: CCOC(=O)/C=C(\NC)c1ccccc1
Reactant: COc1cc(N)ccc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C(\Nc1ccc(Br)c(OC)c1)c1ccccc1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of ethyl (2Z)-3-(methylamino)-3-phenylacrylate (4.47 g, 21.77 mmol) in DCM (100 mL) was added 4-bromo-3-methoxyaniline (4 g, 19.80 mmol) and PPTS (5.47 g, 21.77 mmol). The mixture was then heated to reflux for 24 h. At this time crude 1H NMR revealed nearly complete consumption of the aniline. The reaction was then cooled to RT, filtered, and the solvent was removed in vacuo. The crude product was purified on silica (75% DCM/hexanes) to yield ethyl (2Z)-3-[(4-bromo-3-methoxyphenyl)amino]-3-phenylacrylate (6.5 g, 87%) which was used as is in subsequent reactions. 1H NMR (500 MHz, CDCl3) ppm: 10.32 (br s, 1H), 7.32 (m, 5H), 7.20 (d, J=8.5 Hz, 1H), 6.19 (dd, J=8.5 Hz, 2.5 Hz, 1H), 6.11 (d, J=2.5 z, 1H), 5.03 (s, 1H), 4.21 (q, J=7.0 Hz, 2H), 3.50 (s, 3H), 1.32 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](C1C=CC(NN)=CC=1)#[N:21]>>[NH2:19][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:20]#[N:21])=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Product: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Yield: 85 %

Procedure:
The title compound was prepared (85% yield) in the same manner as described for 5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-ylamine, replacing 4-nitrophenylhydrazine with 4-cyanophenylhydrazine. MS LC-MS [M+H]+=241, RT=2.39 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][OH:15])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1conc1-c1ccc(F)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 3-(3-chloro-4-fluorophenyl)isoxazole-4-carboxylate (9.70 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(3-chloro-4-fluorophenyl)-4-isoxazolylmethanol (7.91 g, yield 97%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O.CO.CC(C)=O>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:7][CH3:6])=[O:18]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)CCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CCCCCCC(=O)OCC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Add a solution of sodium bicarbonate (2.12 g, 25.2 mmol) in water (10 mL) to a solution of suberic acid monomethyl ester (4.75 g, 25.2 mmol) in methanol (50 mL) at room temperature and stir the mixture for 30 minutes. Remove the solvent under reduced pressure and add the residue to a solution of 2-bromoacetophenone (5.0 g, 25.1 mmol) in acetone (150 mL) at room temperature under nitrogen. Heat the mixture at reflux for 10 hours and then remove the solvent under reduced pressure. Dilute the residue with diethyl ether (300 mL), stir for 20 minutes, filter through a short silica gel column, and wash with diethyl ether (2×50 mL). Remove the solvent under reduced pressure to provide octanedioic acid methyl ester 2-oxo-2-phenylethyl ester (6.9 g, 90%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][N:25]([CH2:3][C:4]2[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([NH2:16])[C:7]=3[N:17]=2)[CH2:26][CH2:27]1
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Reactant: C1COCCN1
Agent: Cl
Product: Nc1nc2ccccc2c2c1nc(CN1CCOCC1)n2Cc1ccccc1
Temperature: 25 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 2.0 g of the alcohol) was added to morpholine (5.0 mL) and the mixture was refluxed for 4 hr. The mixture was then cooled to room temperature and the solid was filtered from the mixture. The solid was slurried in aqueous sodium bicarbonate solution, filtered from the mixture, and dried. A crude yield of 2.0 g of product as a white solid was obtained. The crude product was recrystallized from methanol/dichloromethane. m.p. >300° C. Analysis: Calculated: C, 70.7; H, 6.2; N, 18.8. Found: C, 70.4; H, 6.2; N, 18.6.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:6]=1.C[Al](C)C.[CH3:22][C:23]([Si:26]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38](OC)=[O:39])=[CH:33][CH:32]=[CH:31]2)([CH3:25])[CH3:24].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:25][C:23]([Si:26]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38]([NH:17][C:9]1[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=[C:7]([N:5]3[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]3)[CH:8]=1)=[O:39])=[CH:33][CH:32]=[CH:31]2)([CH3:22])[CH3:24]
Reactant: COC(=O)c1cccc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(NC(=O)c3cccc4cc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)ccc34)cc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Under an argon atmosphere, a stirred solution of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzenamine (0.99 g, 4.1 mmol) in dry toluene (40 mL) is treated with a solution of AlMe3 (5 mL of 2 M in toluene; 10 mmol) at 40° C. After 45 min, a solution of 6[[(1,1-dimethylethyl)diphenylsilyl]oxy]-1-naphthalenecarboxylic acid, methyl ester (1.64 g, 3.72 mmol) in dry toluene (15 mL) is added and the stirred mixture is heated at 100° C. for 90 min. The cooled mixture is then added to a saturated aqueous solution of NH4Cl and stirred for 30 min. The organic phase is separated, washed with brine, dried (Na2SO4) and solvent is evaporated off under reduced pressure to give a residue, which is purified by column chromatography (SiO2; hexane/ethyl acetate 1:1) to afford the title compound as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][C@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
3-Bromo-4-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 10.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (32.2 mg, 0.260 mmol), Pd(PPh3)2Cl2 (9.11 mg, 0.013 mmol) and Na2CO3 (55.0 mg, 0.519 mmol) were added to a MW vial and treated with a mixture of DME (551 μL), water (157 μL) and EtOH (79 μL). Vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 54.1 mg, 0.078 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, isocratic 25% in 9 min.) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=0.83 min, m/z=462.1 [M+H]+, m/z=460.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=10.76, 4.16 Hz, 2H) 3.26 (dd, J=10.51, 4.89 Hz, 2H) 3.98 (t, J=3.91 Hz, 2H) 4.89 (br. s, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:4]=[C:5]([S:14][CH3:15])[N:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[NH2:1][C:3]1[N:4]=[C:5]([S:14][CH3:15])[N:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: N
Product: CCOC(=O)c1nnc(SC)nc1N

Procedure:
can be prepared if ammonia is used to displace the chloro group of 5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester to give 5-amino-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester. The aldehyde is obtained and reacted with a substituted phenyl acetonitrile as described above to provide the 6-amino-pyridotriazines. The methylthio group is displaced as described above, also, and the 6-amino group of the resulting 6-amino-7-substituted phenyl-3-substituted amino-pyrido-1,2,4-triazine is derivatized by standard methods, for example alkylation or acylation, to provide compounds of Formula III.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11]NC(=O)C2C=CC(N3CCN(CC4C=NC=CC=4)CC3)=CC=2)=[CH:9][CH:8]=1)=[O:4].C(OC(=O)C=CC1C=CC(C[S:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:51])=[O:50])=CC=1)C>>[C:52]1([S:49]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:3]([NH:2][OH:1])=[O:4])=[CH:35][CH:34]=2)(=[O:51])=[O:50])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CCOC(=O)C=Cc1ccc(CS(=O)(=O)c2ccccc2)cc1
Reactant: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Product: O=C(C=Cc1ccc(CS(=O)(=O)c2ccccc2)cc1)NO
Yield: 52 %

Procedure:
The titled compound was prepared as described in the process (1-3) using the compound from the process (10-4).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH2:12][C:13]4[S:14][CH:15]=[CH:16][C:17]=4[C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(O)(=O)C>[Br:18][C:16]1[C:17]2[C:10]3[NH:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]=3[CH2:12][C:13]=2[S:14][CH:15]=1
Reactant: c1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1csc2c1-c1[nH]nc(-c3ccccc3)c1C2
Temperature: 80 °C
Yield: 88 %

Procedure:
6-Phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.12 g, 0.5 mmol) was added with a solution of bromine in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated at 80° C. for 12 hr. The solution was cooled to room temperature and poured into ice water. The resultant precipitate was filtered, washed with water to provide the corresponding 3-Bromo-6-phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.14 g, 0.44 mmol) as yellow solid in 88% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Brc1cccc2cnccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cc(N2CCNCC2)c2ccncc2c1
Temperature: 90 °C
Yield: 62.5 %

Procedure:
5-Bromoisoquinoline (250 mg, 1.2 mmol) is dissolved in toluene (5 mL). To the solution is added piperazine (258 mg, 3.0 mmol), Pd2dba3 (55 mg, 0.06 mmol), BINAP (112 mg, 0.18 mmol), and sodium t-butoxide (162 mg, 1.68 mmol). The mixture is degassed and then heated to 90° C. for about 12 hours. The reaction is allowed to cool to r.t., diluted with diethyl ether and filtered through celite. The filtrate is concentrated, and the dark residue is chromatographed on silica gel to give about 160 mg of 5-(piperazin-1-yl)isoquinoline (63%). EIS-MS: Found 214.0 (M+1).
Reaction SMILES: Cl/[C:2](=C/N(C)C)/[C:3](C1N(C(C)C)C(C)=NC=1)=[O:4].S([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:50]=[CH:49][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:46])[CH3:45])[C:42]([CH3:47])=[N:41][CH:40]=4)[C:36]([Cl:48])=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(C)(=O)=O>COCCO>[C:3]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:50]=[CH:49][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:45])[CH3:46])[C:42]([CH3:47])=[N:41][CH:40]=4)[C:36]([Cl:48])=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(=[O:4])[CH3:2]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)ncc2Cl)n1C(C)C
Reactant: Cc1ncc(C(=O)/C(Cl)=C\N(C)C)n1C(C)C
Solvent: COCCO
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(Cl)c(-c4cnc(C)n4C(C)C)n3)cc2)CC1

Procedure:
(2E)-2-Chloro-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (1.68 g from Method 3-assumed 5 mmol) and N-[4-(4-acetylpiperazin-1-yl)phenyl]guanidine bicarbonate salt (Method 2) (1.94 g 6 mmol) in 2-methoxyethanol (25 ml) were heated under nitrogen at 110° C. for 3.5 hours before evaporation under reduced pressure. The residue was purified by chromatography on silica gel with MeOH:DCM (3:97 to 5:95) to give the title compound, after trituration with ether, as a foam. NMR: 1.36 (d, 6H), 2.02 (s, 3H), 2.48 (s, 3H), 3.00 (b t, 2H), 3.08 (b t, 2H), 3.56 (b q, 4H), 4.80 (septuplet, 1H), 6.90 (d, 2H), 7.21 (s, 1H), 7.47 (d, 2H), 8.50 (s, 1H), 9.48 (s, 1H); m/z 454.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O:23][C:24]1[C:25](=[O:56])[C:26](=O)[C:27]=1[NH:28][C:29]1[CH:30]=[N:31][N:32]([CH3:54])[C:33]=1[NH:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C.C(N(CC)CC)C>C(O)C>[CH3:54][N:32]1[C:33]([NH:34][C:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([NH:28][C:27]2[C:24](=[O:23])[C:25](=[O:56])[C:26]=2[NH:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:30]=[N:31]1
Reactant: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Reactant: CCOc1c(Nc2cnn(C)c2NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1ncc(Nc2c(NC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c(=O)c2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
To a suspension of di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (810 mg) and 3-ethoxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-cyclobutene-1,2-dione (957 mg) in ethanol (10 ml) was added triethylamine (0.279 ml), and the mixture was stirred under reflux for 1 day. The reaction mixture was concentrated to about 5 ml in vacuo. To the concentrate was added diisopropyl ether. The precipitated crystals were collected by filtration and dried in vacuo to give di-tert-butyl {2-[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]-1,3-propanediyl}biscarbamate (1.22 g) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[Cl:21].Br[C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][C:13]2[C:3]([CH2:2][NH:1][C:23]3[CH:24]=[CH:25][C:26]([C:27](=[O:28])[NH:29][CH:30]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:37][CH:38]=3)=[C:4]([Cl:21])[CH:5]=[CH:6][C:7]=2[CH2:8][CH2:9]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CN)c2CC1
Reactant: O=C(NC1CCCCCC1)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CNc3ccc(C(=O)NC4CCCCCC4)cc3)c2CC1
Temperature: 70 °C
Yield: 54.6 %

Procedure:
Under a nitrogen atmosphere, add 6-aminomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.6 mmol), 4-bromo-N-cycloheptyl-benzamide (520 mg, 1.8 mmol), palladium(II) acetate (35 mg, 0.16 mmol), BINAP (150 mg, 0.24 mmol) and sodium-t-butoxide (460 mg, 4.8 mmol) to toluene (10 mL). Heat the mixture at 70° C. for 1 h. Cool the mixture to room temperature and dilute with water and DCM. Separate the layers and extract the aqueous phase with DCM. Wash the combined organic extracts with water and brine. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 17:1 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-[(4-cycloheptylcarbamoyl-phenylamino)-methyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (460 mg, 54%). MS (APCI+) m/z: 526 (M+H)+.