Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([SiH3:8])(OC)OC.C(O[CH2:12][CH3:13])C.[CH2:14]([Si:17]([CH2:26][CH:27]=[CH2:28])([CH2:23][CH:24]=[CH2:25])[CH2:18][CH2:19][CH2:20][Mg]Br)[CH:15]=[CH2:16].Cl>O>[CH2:14]([Si:17]([CH2:26][CH:12]=[CH2:13])([CH2:18][CH:19]=[CH2:20])[CH2:23][CH2:24][CH2:25][SiH:8]([CH2:20][CH2:19][CH2:18][Si:17]([CH2:26][CH:27]=[CH2:28])([CH2:14][CH:15]=[CH2:16])[CH2:23][CH:24]=[CH2:25])[CH2:3][O:2][CH3:1])[CH:15]=[CH2:16]
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Mg]Br
Reactant: COC([SiH3])(OC)OC
Reactant: CCOCC
Agent: Cl
Solvent: O
Product: C=CC[Si](CC=C)(CC=C)CCC[SiH](CCC[Si](CC=C)(CC=C)CC=C)COC
Temperature: 0 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, trimethoxymethylsilane (18) (42 μl, 0.3 mmol) was added into a reaction container, cooled down to 0° C. and then diethyl ether solution of 0.9M 3-(triallylsilyl)propylmagnesium bromide (24) (1 mL, 0.9 mmol) was dropped. After dropping, stirring was continued at room temperature for 5 hours. To the reacted mixture, water was added to stop the reaction, then 10% hydrochloric acid was added until the salt was completely dissolved. The obtained organic layer was separated and the obtained water layer was extracted with diethyl ether. The collected organic layer was washed each with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, then dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, obtaining bis{3-(triallylsilyl)propyl}(methoxy)methylsilane (35) represented by the following chemical reaction equation (yield: 85 mg, yield (%): 62%).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:7]([O:9][CH3:10])=[O:8].[H][H]>C(O)C.[Pd]>[NH2:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:17]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N)c(OC(F)F)c1
Yield: 75.9 %

Procedure:
Methyl 3-(difluoromethoxy)-4-nitrobenzoate (0.9 g) was placed in a 250 mL round bottom flask and dissolved in 30 mL of ethanol. Pd/C (0.15 g, 10% Pd) was carefully added and a balloon of hydrogen was attached to the flask. The reaction was vigorously stirred over night. After checking by TLC, the reaction was filtered through a pad of celite and concentrated to give 0.6 g of methyl 4-amino-3-(difluoromethoxy)benzoate which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[CH:18](OCC)=[O:19]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:18]=[O:19])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CN)ccc1Br
Reactant: CCOC=O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC=O)ccc1Br

Procedure:
To a solution of 4-bromo-3-methyl-benzylamine (15.11 g) (Example I1) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.49 (m, 1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][C:52]=1[F:53])[C:48]#[N:49]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:46]=[C:47]([CH:50]=[CH:51][C:52]=3[F:53])[C:48]#[N:49])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1ccc(F)c(N)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cc(C#N)ccc3F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 3-amino-4-fluoro-benzonitrile according to procedure B followed by deprotection yielded the title compound as a pale yellow solid. MS (ESI): m/z=398.2 [M+H]+.
Reaction SMILES: CS(O[CH:6]([C:8]1[C:9]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:10][C:11]2[N:12]([C:18](=[O:33])[NH:19][C:20]3[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=3)[CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=1)[CH3:7])(=O)=O.[CH3:39][NH2:40]>C(Cl)Cl.CN(C=O)C.O>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:18]([N:12]2[C:11]3[C:16](=[CH:17][C:8]([CH:6]([NH:40][CH3:39])[CH3:7])=[C:9]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:10]=3)[CH2:15][CH2:14][CH2:13]2)=[O:33])=[N:21][CH:22]=1)#[N:32]
Reactant: CN
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)OS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CNC(C)c1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Temperature: 25 °C

Procedure:
To a suspension of (racemic) 1-(8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl methanesulfonate (intermediate 182, 231 mg, 0.421 mmol) in DCM (8 ml) and DMF (0.5 ml) at 0° C. was added methylamine (2M in THF, 3 mL, 6.00 mmol). The reaction mixture was allowed to warm to room temperature and continued to stir over night. The reaction mixture was diluted with water and DCM, phases were separated and the water phase was extracted with DCM (3×), organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with MeOH (including 3% NH3, 4-5%) in DCM to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.76 min, ESI-MS 484.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 5.42 (s, 1H), 5.25 (t, 1H), 4.80-4.70 (m, 1H), 4.11-3.93 (m, 2H), 3.62 (t, 2H), 3.52-3.42 (m, 8H), 3.39 (s, 3H), 2.99-2.81 (m, 2H), 2.38 (s, 3H), 2.05-1.93 (m, 2H), 1.54 (d, J=6.6 Hz, 3H), 1.24 (s, 1H).
Reaction SMILES: O[N:2]=[C:3]([NH2:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]2)=[CH:6][CH:5]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH2:24])=[NH:2])=[CH:5][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=NO)c1ccc(OCCCN2CCC(CCCO)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OCCCN2CCC(CCCO)CC2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 88.5 %

Procedure:
To an acetic acid (80 mL) suspension of 10.0 g of N′-hydroxy-4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzamidine were added 5.31 mL of acetic anhydride and 0.50 g of 5% palladium-carbon at room temperature, which was stirred at room temperature under hydrogen atmosphere for 12 hours and 50 minutes. After filtering off insoluble matter, the solvent was distilled off under reduced pressure. To the resultant residue was added 6 mol/L hydrochloric acid, followed by distilling off the solvent under reduced pressure before purification using silica gel column chromatography (silica gel: ODS-A from YMC, eluent; water). The eluate was concentrated to about 100 mL under reduced pressure and then adjusted to pH 12 using a 5 mol/L sodium hydroxide aqueous solution. The precipitate was collected by filtration and washed with water to provide 8.43 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [C:1]1(B(O)O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.O.[C:20]([OH:24])(=[O:23])[CH:21]=O.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]1([CH:21]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[C:20]([OH:24])=[O:23])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: OB(O)C1=CCCC1
Reactant: O=CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)C(C1=CCCC1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.45 mmol) of cyclopent-1-en-1-ylboronic acid, 59.5 mg (0.45 mmol) of 1,2,3,4-tetrahydroisoquinoline and 41 mg (0.45 mmol) of glyoxalic acid monohydrate were initially charged in 2 ml of dichloromethane, and 78 μl (57 mg, 0.45 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred at RT for overnight and then concentrated under reduced pressure. The residue was purified by preparative HPLC (RP18 column; acetonitrile/water gradient with addition of 0.1% TFA, 10:90→95:5; run time 38 min) 101 mg (91% purity, 80% of theory) of the title compound were obtained.
Reaction SMILES: C([NH:3][C@@:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:5]([OH:7])=[O:6])=O.C(N[C@:18](C1C=CC=CC=1)(C)[C:19](O)=O)=O>>[NH2:3][C@@:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: C[C@@](NC=O)(C(=O)O)c1ccccc1
Reactant: C[C@](NC=O)(C(=O)O)c1ccccc1
Product: CCOC(=O)[C@](C)(N)c1ccccc1

Procedure:
The title compound was prepared (1.12 g, 76%) by the procedure of Example 445C substituting the product of Example 450A for the product of Example 445B.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][N:29]([CH3:44])[CH2:28]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCNC5)ccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCN(C)C5)ccn34)c12
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To N3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-N7-(pyrrolidin-3-yl)imidazo[1,2-a]pyridine-3,7-dicarboxamide (5 mg, 0.0096 mmol; prepared as in Example 46) in DCM/MeOH (1 mL/1 mL) was added HCHO as a 35% aqueous solution (16 mg, 0.19 mmol) and NaBH(OAc)3 (10 mg, 0.048 mmol). The reaction mixture was stirred for one hour, concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=537 (M+H).
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[H-].[Na+].[C:39]([O:43][C:44]([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55]Br)=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.[Cl-].[Na+].O>[C:39]([O:43][C:44]([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55][CH:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5](=[O:28])[N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:16]2=[O:17])=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (520 mg, 1.079 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in oil, 50 mg, 1.27 mmol). The reaction was stirred at 0° C. for 45 minutes and 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (423 mg, 1.36 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 24 hours and was diluted with brine. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (1×), dried (MgSO4), filtered and concentrated in vacuo to provide 3-(6-{[isopropyl-(6-methoxy-pyridin-3-yl)-carbamoyl]-methyl}-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl)-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD3OD) δ 8.05 (d, 1H), 6.80-7.75 (m, 15H), 4.75 (m) and 4.60 (t, total 3H), 3.85-4.20 (m, 6H), 1.65 (m, 9H), 0.98 (m, 6H); MS 713.6 (M+1), 711.5 (M−1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]1[C:18]2[O:17][C@@H:16](NC)[CH2:15][C:14]=2[CH:13]=[C:12]([F:21])[CH:11]=1.[CH:22]([N:25]([CH:28](C)C)CC)(C)[CH3:23].C(OC(=O)C)(=[O:33])C>C(Cl)Cl>[Cl:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=1[C:10]1[C:18]2[O:17][C@@H:16]([CH2:28][NH:25][C:22](=[O:33])[CH3:23])[CH2:15][C:14]=2[CH:13]=[C:12]([F:21])[CH:11]=1
Reactant: CN[C@H]1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)NC[C@H]1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
(R)-[7-(2,6-Dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-yl]-methylamine hydrochloride (0.050 g, 0.14 mmol) was suspended in 5.0 mL of methylene chloride and diisopropylethylamine (0.072 g, 0.56 mmol) and acetic anhydride (0.029 g, 0.28 mmol) added. The mixture was stirred at room temperature for 30 min, diluted to 100 mL with methylene chloride, washed with 50 mL portions of 2 N HCl (aqueous), saturated aqueous sodium bicarbonate and saturated brine. The solution was dried over sodium sulfate, filtered and concentrated in vacuum to give 0.043 g of the title compound as a white crystalline solid. 1H-NMR (CDCl3): multiplet 7.4 δ (1H); multiplet 7.33 δ (2H); doublet 6.95 δ (1H); doublet 6.72 δ (1H); broad singlet 5.8 δ (1H); multiplet 4.9 δ (1H); doublet of doublets 3.6 δ (1H); doublet of doublets 3.47 δ (1H); doublet of doublets 3.38 δ (1H); doublet of doublets 3.0 δ (1H); singlet 1.9 δ (3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:12]2[N:17]3[N:18]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(O)[CH3:10])[CH:6]=[CH:5][N:4]=1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]2[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH:9]([C:7]4[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=4)[CH3:10])[N:17]3[N:18]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(C(C)(O)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(c1cc[nH]c(=O)c1)c1cccc2nc(Nc3ccc(C(F)(F)F)cc3)nn12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 93 %

Procedure:
1-(2-Methoxypyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethanol. Methylmagnesium bromide (1.390 mL, 4.17 mmol, 3 M solution in diethyl ether) was added dropwise to a stirred solution of (2-methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methanone (0.431 g, 1.043 mmol) in tetrahydrofuran (20 mL) at 0° C. under nitrogen. The reaction instantly became red-colored upon addition of the methylmagnesium bromide but then became more yellow-colored. The resulting mixture was stirred at 0° C. under nitrogen for 50 min. Saturated aqueous ammonium chloride (2 mL) was added to quench the reaction. The resulting mixture was diluted with water and ethyl acetate and shaken in a separatory funnel. The layers were separated. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was dissolved in dichloromethane and purified using flash chromatography (Biotage) (20-90% ethyl acetate in hexane) to give the desired product (0.417 g, 0.971 mmol, 93% yield) as a yellow foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.01 (s, 1H), 8.06 (d, J=5.47 Hz, 1H), 7.74 (dd, J=7.42, 8.59 Hz, 1H), 7.61 (dd, J=1.17, 8.98 Hz, 1H), 7.50-7.59 (m, 4H), 7.47 (dd, J=1.17, 7.42 Hz, 1H), 6.94 (d, J=0.78 Hz, 1H), 6.86 (dd, J=1.56, 5.47 Hz, 1H), 6.44 (s, 1H), 3.82 (s, 3H), 2.03 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ (ppm)-60.20 (s, 3F); MS (ESI) m/z 430.3 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:18]([OH:24])(=[O:23])[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:20]([C:19]([C:18]([OH:24])=[O:23])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:22])=[O:21]
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)C(=Cc1ccc(-c2ccc(-c3cccs3)s2)s1)C(=O)O
Yield: 83.9 %

Procedure:
1.30 g of 5-formyl-2,2':5',2"-terthiophene, 1.04 g of malonic acid, 20 ml of pyridine and 0.1 ml of piperidine were heated at 50°-60° C. for 2 hours. 100 ml of water was added after reaction was completed. The mixture was acidified by diluted HCl and the precipitate collected was recrystallized from ethanol to give reddish crystal (1.43 g). The melting point thereof was 202°-203° C. The yield was 84%.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:31][S:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>C(O)CCC.C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][S:32][CH3:31])[CH:35]=2)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Reactant: CSCc1cccc(N)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: C1COCCO1
Product: CSCc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 27.4 %

Procedure:
A 4N solution of hydrogen chloride in dioxane (0.34 mL; 1.35 mmol) was added to a stirred solution of 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (450 mg; 1.35 mmol) and 3-[(methylsulfanyl)methyl]aniline (311 mg; 2.03 mmol) in 1-butanol (3.00 mL). The batch was stirred at 140° C. for 16 hours. After cooling the batch was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (167 mg; 0.37 mmol).
Reaction SMILES: [OH-].[Zn+2:2].[OH-].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10]>C(O)C>[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[Zn+2:2].[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [OH-]
Agent: [Zn+2]
Solvent: CCO
Product: NCCCC[C@H](N)C(=O)[O-]
Reaction time: 3 h

Procedure:
The zinc hydroxide precipitate was then placed into a beaker provided with a reflux condenser and 29.2 grams (0.2 Mole) of lysine was added. 100 ml ethanol was then added to this mixture and stirred and boiled at atmospheric pressure for 3 hours. The reaction mixture was then cooled and filtered yielding 35.5 grams of zinc lysinate in the form of a fine white powder.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]C(C)(C)C)=[O:9])[C:6](=[O:7])[CH2:5][CH2:4][O:3]1.F[C:16](F)(F)C(O)=O.ClCCl>>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[C:6](=[O:7])[CH2:5][CH:4]([CH3:16])[O:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(C)OCCC1=O
Solvent: ClCCl
Product: CC1CC(=O)C(C)(C(=O)O)O1
Temperature: 25 °C
Yield: 68 %

Procedure:
2-Methyl-3-oxo-2-tetrahydrofuroic acid, t-butyl ester (100 mg, 0.5 mmol) was treated with 1/1 trifluoroacetic acid/dichloromethane at 0° C. The reaction mixture was stirred at room temperature until all starting material had disappeared by TLC. The excess trifluoroacetic acid was removed via a stream of nitrogen and the residue was coevaporated with dichloromethane and purified via a silica gel SepPak plug. This 30 provided 49 mg of the desired product (68%), homogeneous by TLC (Rf=0.1 in 4/1 hexane/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 4-methylsulfonylbenzenesulfonylchloride (61 mg, 0.455 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 551.2. Calcd: 551.10.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
3-Fluoronitrobenzene (10 g, 71 mmol) was dissolved in acetonitrile (100 mL). Morpholine (30 mL, 350 mmol) was added and the mixture was reacted 18 h at 150° C./80 psi in a pressure reactor. The reaction was cooled to room temperature, concentrated under vacuum and 5 g of the total mixture was purified by column chromatography on silica eluted with CH2Cl2. The product (3.6 g) was isolated as a bright yellow oil.