Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1ccc(F)cc1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (1.7 g, 12.85 mmole) and 4-fluorobenzoyl chloride (2.24 g, 14.1 mmole) as in Ex. 52; 1.71 g (6.7 mmole, 52%), mp: 109°-10° C.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(N(CC)CC)C>[C:26]([N:13]([C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])[C:14](=[NH:17])[S:15][CH3:16])([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSC(=N)N(C(=O)OCc1ccccc1)C(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-pseudothiourea hydroiodide (II, 494 mg, 1.27 mmol) was dissolved in a mixture of anhydrous DMF (10 mL), and triethylamine (3 mL) followed by treatment with N-(benzyloxycarbonyloxy) succinimide (470 mg, 1.7 mmol) dissolved in DMF (3 mL). The reaction mixture was stirred overnight at room temperature. After this time, the reaction mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate (30 mL). Silica gel (25 g) was added to the solution and the solvent was evaporated to leave the silica gel impregnated with the crude product that was purified by flash chromatography on a FlashElute™ system from Elution Solution (P.O. Box 5147, Charlottesville, Va. 22905) using a 90 g silica gel cartridge (eluent: hexanes, ethyl acetate=1:2). The purified N-Cbz-1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-pseudothiourea (III) was obtained as a pale yellow solid: 416 mg (83% yield); 1H NMR (360 MHz, DMSO-d6) δ 2.33 (s, 3H), 2.61 (s, 3H), 4.99 (s, 2H), 7.39 (m, 10H), 13.7 (s, 1H); API MS m/z=395 [C15H15ClN6O3S+H]+; LC/MS (Method A)>99%, tr=10.1 min.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[S:8][C:9](/[CH:20]=[C:21](\[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)/[C:22]([OH:24])=[O:23])=[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[CH:5]=1.[OH-].[Na+:36]>>[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[S:8][C:9](/[CH:20]=[C:21](\[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)/[C:22]([O-:24])=[O:23])=[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:6]=2[CH:5]=1.[Na+:36]
Reactant: COc1ccc(Oc2c(/C=C(/C(=O)O)c3ccncc3)sc3cc(OC)c(OC)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Oc2c(/C=C(/C(=O)[O-])c3ccncc3)sc3cc(OC)c(OC)cc23)cc1

Procedure:
Water is added to a suspension of 1.16 g of the product of Example 2 in 2.5 ml of 1N sodium hydroxide solution until completely diluted. Lyophilisation enables 1.22 g of the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:18])[N:12]=[C:13]([N:15](C)C)[CH3:14])[CH2:7][CH2:6]1)=[O:4].N1C=CC=CC=1.NOS(O)(=O)=O>C(O)C.CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[S:18][N:15]=[C:13]([CH3:14])[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=S)N=C(C)N(C)C)CC1
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H](c2nc(C)ns2)CC1

Procedure:
To a solution of trans-4-[1-dimethylamino-ethylidenethiocarbamoyl]-cyclohexanecarboxylic acid methyl ester (0.87 g, 3.2 mmol) and pyridine (0.52 ml, 6.5 mmol) in ethanol (6 ml) was added a solution of hydroxylamine-O-sulfonic acid (0.45 g; 3.6 mmol) in methanol (3 ml) at room temperature. After stirring over night the reaction mixture was partitioned between 1 M aqueous hydrochloric acid solution (100 ml) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with one 100-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.68 g, 88%) as yellow oil. MS m/e: 241 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].CO>O1CCCC1.C(N(CC)CC)C>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cccc(-c2cccnc2)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A cooled (−78° C.) solution of 3-(3-bromophenyl)pyridine (7.50 g, 32 mmol) in tetrahydrofuran (120 ml) was treated with a cooled (−78° C.) solution of tert-butyllithium (41 ml of a 1.7M solution in hexanes, 70 mmol). After 5 minutes tri-n-butyltin chloride (9.6 ml) was added and the mixture was allowed to warm to room temperature over 1 h. Methanol (7.5 ml) and triethylamine (7.5 ml) were added and the solvent evaporated. The residue was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution, the organics washed with brine, dried and evaporated to give a yellow oil. This oil was purified by silica gel flash column chromatography eluting with isohexane/ethyl acetate/triethylamine (99:1:0.5 through to 80:20:0.5) to afford 3-[3-(tri-n-butylstannanyl)phenyl]pyridine (11.7 g, 82%) as a colourless oil. 1H NMR (360 MHz, CDCl3) δH 0.86-0.93 (3H, m), 1.06-1.12 (2H, m), 1.28-1.40 (2H, m), 1.54-1.56 (2H, m), 7.34-7.39 (2H, m), 7.48-7.52 (2H, m), 7.62-7.65 (1H, m), 7.83-7.88 (1H, m), 8.57-8.60 (1H, m), 8.85 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])[CH:23]=[C:22]([Cl:32])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)=O)=[CH:11][CH:10]=1.Cl.[CH2:34]([O:36][NH2:37])[CH3:35]>N1C=CC=CC=1>[CH2:34]([O:36][N:37]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:25][C:24]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])=[CH:23][C:22]=2[Cl:32])=[CH:10][CH:11]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[CH3:35]
Reactant: CCON
Reactant: O=C(c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1)c1ccon1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1)c1ccon1

Procedure:
486 mg of (4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-isoxazol-3-yl-methanone in 25 ml of pyridine are stirred with 184 mg of O-ethylhydroxylamine hydrochloride at 110° C. for 24 hours. The reaction mixture is concentrated and the residue is stirred with tert-butyl methyl ether and 0.5N hydrochloric acid. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([O:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:32])=[C:23]([NH:25]C(=O)C(F)(F)F)[CH:24]=1)[N:12]=2)(=[O:7])[CH3:6]>C(O)C.C(OCC)(=O)C>[NH2:25][C:23]1[CH:24]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:32])[O:18][C:13]1[N:12]=[C:11]2[S:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:17][C:16]2=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(N)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
Sodium borohydride (2.45 g, 64.8 mmol) was suspended in ethanol (43 mL), and methanol (29 mL) was slowly added. To the obtained reaction mixture was added N-(5-{[2-(acetylamino)[1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-2-chlorophenyl)-2,2,2-trifluoroacetamide (1.5 g, 3.48 mmol) powder in small portions under cooling in a water bath, and then, the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL), and partitioned with water (50 mL), and the organic layer was concentrated under reduced pressure. The residue was diluted with ethyl acetate (80 mL), and washed with saturated brine (80 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and triturated with diisopropyl ether to give the title compound (0.58 g, 50%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:17]1([C:21]([C:23]2[CH:24]=[C:25]([Cl:30])[C:26](Cl)=[N:27][CH:28]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:17]1([C:21]([C:23]2[CH:24]=[C:25]([Cl:30])[C:26]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:27][CH:28]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@@H](C)CO)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 121.2 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (2.35 g, 10.39 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.41 g, 10.39 mmol) and potassium carbonate (2.87 g, 20.8 mmol) in acetonitrile (20 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo. The crude oil was chromatographed on silica, eluting with 30-100% ethyl acetate in isohexane, to give the desired compound as a yellow oil (5.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C=O)C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C=O)C1
Yield: 101.7 %

Procedure:
To the title compound of Example 1 Step B (0.20 g, 0.56 mmol), 2-trifluoromethylphenylboronic acid (0.16 g, 0.84 mmol), K3PO4 (0.357 g, 1.68 mmol) Pd(dba)2 (0.013 g, 0.022 mmol) and Q-Phos (0.008 g, 0.011 mmol) was added PhCH3. After 48 h at rt the reaction was diluted with EtOAc and filtered through a small silica pad. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.24 g (99% yield) of the title compound. MS (ESI): mass calcd. for C22H22F3NO4, 421.15; m/z found, 336.1 [M-56]+, 444.1 [M+Na]+. 1H NMR (CDCl3): 10.53 (d, J=0.7 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 6.59 (s, 1H), 4.99 (tt, J=6.4, 4.0 Hz, 1H), 4.37-4.29 (m, 2H), 4.11-4.08 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
To a solution of 4-butylbenzylamine (4.01 g, 24.6 mmol) in CH2Cl2 (75 mL) was added pyridine (4.0 mL, 49 mmol) followed by dropwise addition of methanesulfonyl chloride (2.5 mL, 32.3 mmol). The reaction was stirred at room temperature for 24 h and water was added. The product was extracted into CH2Cl2 (2×) and the organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (2:1 to 1:1 hexanes:EtOAc) provided the title compound as a white solid (3.4114 g). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, 2H), 7.15 (d, 2H), 4.84 (m, 1H), 4.25 (d, 2H), 2.82 (s, 3H), 2.58 (t, 2H), 1.56 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Mg+2:40].[OH-]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Mg+2:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.050 g, 0.091 mmol) in ethanol (5 mL) was added magnesium hydroxide (7.97 mg, 0.137 mmol) in 1 mL of water. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was washed with ethyl acetate (2×5 mL), acetone (2×10 mL) and acetonitrile (2×10 mL) to afford magnesium(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (8) (0.040 g, 0.069 mmol, 76% yield) as a yellow solid. 1H NMR was not taken because of poor solubility. LCMS Method I: retention time 1.66 min, [M−1]=547. HPLC Method B: Purity 98.1%, retention time 6.18 min, HPLC Method C: Purity 95.6%, retention time 5.98 min. Elemental analysis: MF C25H20N6SPO5.Mg H2O, Calculated C, 46.15; H, 4.41; N, 12.92; Mg, 4.15; H2O, 11.70. Found C, 40.66; H, 4.12; N, 11.23; Mg, 4.14; H2O, 11.70; C and N are not in agreement.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:27][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:13]=[C:14]([C:17]([O:19]C)=O)[C:15](=[O:16])[C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:17]([C:14]2[C:15](=[O:16])[C:10]3[CH:9]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[S:27][C:11]=3[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:13]=2)=[O:19])=[CH:31][CH:30]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of methyl 6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxylate (0.29 g) in 4-chlorobenzylamine (2 mL) is heated to 190° C. for 30 min. The reaction mixture is cooled to ambient temperature, the solvent is removed in vacuo and Et2O (15 mL) is added to the residue. The resulting precipitate is filtered and rinsed with Et2O to afford 0.24 g (65%) of the title compound as a tan solid. Physical characteristics: m.p. 182-184° C.; 1H NMR (400 MHz, CDCl3) δ10.56, 7.71, 7.58, 7.42, 7.32, 4.69, 3.71, 3.65, 2.51; IR (diffuse reflectance) 1677, 1587, 1549, 1532, 1508, 1493, 1347, 1297, 1278, 1261, 1115, 1112, 799, 777, 701 cm1; MS (EI) m/z 494 (M+); HRMS (FAB) m/z 495.1265 (C25H23ClN4O3S+H). Anal. Found: C, 60.18; H, 4.79; N, 11.04.
Reaction SMILES: CO/[N:3]=[C:4]1/[C:5]([CH3:18])([CH3:17])[N:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH2:7][CH2:8]/1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[CH3:17][C:5]1([CH3:18])[CH:4]([NH2:3])[CH2:8][CH2:7][N:6]1[CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO/N=C1\CCN(C(=O)c2ccccc2)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)C(N)CCN1Cc1ccccc1
Temperature: 65 °C
Reaction time: 5 h
Yield: 112.9 %

Procedure:
To a solution of (3E)-2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone O-methyloxime (1.9492 g, 7.914 mmol) in THF (80 mL) was added lithium aluminum hydride (0.900 g, 23.72 mmol), and the mixture was heated at 65° C. and stirred for 5 h. The mixture was cooled to 0° C., and Na2SO4.10H2O (2 g) was added. The mixture was stirred for 30 min, and 1 N aq. NaOH (100 mL) was then added. The mixture was extracted with Et2O (3×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude racemic 2,2-dimethyl-1-(phenylmethyl)-3-pyrrolidinamine (1.8247 g, >100% crude yield) as a light yellow oil. LCMS: (M+H)+: 205.2.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CSCc1ccc(N)c(Br)c1
Product: CSCc1ccc(N)c(-c2cccc(Cl)c2)c1

Procedure:
2-bromo-4-(methylthiomethyl)aniline and 3-chlorobenzene boronic acid can be combined to form 2-(3-chlorophenyl)-4-(methylthiomethyl)aniline,
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][N:12]3[C:17]=2[C:16]([NH:18][C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[N:23]=[CH:22]4)=[N:15][CH:14]=[N:13]3)[CH2:4][CH2:3]1.[O:36]1[CH2:40][CH2:39]OC1=O>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][N:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:16]3[C:17]4=[C:9]([CH2:8][N:5]5[CH2:4][CH2:3][CH:2]([NH:1][CH2:39][CH2:40][OH:36])[CH2:7][CH2:6]5)[CH:10]=[CH:11][N:12]4[N:13]=[CH:14][N:15]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: O=C1OCCO1
Solvent: ClCCl
Product: OCCNC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 100 °C

Procedure:
A mixture of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (188 mg, 0.4 mmole) and [1,3]dioxolan-2-one (352 mg, 10 equiv) in a sealed tube was heated at 100° C. for 3.5 h. The title compound was isolated by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (43 mg, 21%); MS: 515 (M+H+); HPLC Ret Time: 1.29 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.ClC1[N+]([O-])=NC([O:14][C:15]2[C:20]([CH:21]=[CH2:22])=[C:19](C)[CH:18]=[C:17](C)[C:16]=2C)=CC=1.[Cl:26][C:27]1N=[N+]([O-])C(OC2C(C=C)=C(C)C=C(C)C=2C)=[CH:31][CH:32]=1>>[Cl:26][CH2:27][CH2:32][CH2:31][CH:22]1[CH2:21][C:20]2[C:19]1=[CH:18][CH:17]=[CH:16][C:15]=2[OH:14]
Reactant: C=Cc1c(C)cc(C)c(C)c1Oc1ccc(Cl)n[n+]1[O-]
Reactant: C=Cc1c(C)cc(C)c(C)c1Oc1ccc(Cl)[n+]([O-])n1
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1cccc2c1CC2CCCCl

Procedure:
0.02 mL (0.22 mmol) of phosphorus oxychloride was added to 27.6 mg (0.0949 mmol) of a mixture of 6-chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide obtained in (6), and the resulting mixture was stirred at room temperature for 2 hours. To the mixture was added 0.4 mL of chloroform, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 0.2 mL (2.2 mmol) of phosphorus oxychloride was added to the residue and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by hexane:ethyl acetate=5:1) to obtain 5.0 mg (0.016 mmol, Yield: 17%) of 4,6-dichloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of Example 1 (0.2 g, 0.66 mmol) in DMF (5 mL) was added triethylamine (0.16 mL, 1.14 mmol) and methyl 3-bromopropionate (0.07 mL, 0.64 mmol). The resulting slurry was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.03 g, 13%); 1H NMR (400 MHz, CDCl3); δ 1.68-1.80 (m, 3H), 1.93-2.04 (m, 1H), 2.29 (q, J=8.4 Hz, 1H), 2.53 (t, J=7.2 Hz, 2H), 2.70 (m, 1H), 2.87 (m, 1H), 3.13 (m, 1H), 3.24 (m, 1H), 3.66 (s, 3H), 3.75 (m, 1H), 3.92 (s, 2H), 3.93 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.16-7.20 (m, 3H), 7.27 (m, 2H); MS (m/z) 354.2 (M+1); LC (100.0%).