Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[C:16]1(C)C=CC=C[CH:17]=1.C(C([Sn])=C(CCCC)CCCC)CCC.[F-].[K+]>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.C(OCC)(=O)C>[F:8][C:7]([F:10])([F:9])[C:6]([NH:5][CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[CH:16]=[CH2:17])=[O:11]
Reactant: O=C(NCc1ccccc1Br)C(F)(F)F
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1CNC(=O)C(F)(F)F
Temperature: 130 °C
Reaction time: 17 h

Procedure:
Under an argon atmosphere, to a mixture of 2.47 g of N-(2-bromobenzyl)-2,2,2-trifluoroacetamide and 25 ml of toluene were added 1.02 g of tetrakis(triphenylphosphine)palladium(0) and 3.10 g of tributylvinyltin, followed by stirring at 130° C. for 17 hours. The reaction mixture was left to be cooled to room temperature, and ethyl acetate and a 10% aqueous potassium fluoride solution were then added thereto, followed by stirring. The reaction mixture was filtered over Celite and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.71 g of 2,2,2-trifluoro-N-(2-vinylbenzyl)acetamide.
Reaction SMILES: [C:1]1([NH2:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.[I-].[K+]>[CH2:14]([N:12]([CH2:9][CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: Nc1cccc2c(N)cccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCCCCCN(CCCCCCCC)c1cccc2c(N(CCCCCCCC)CCCCCCCC)cccc12
Temperature: 110 °C
Yield: 38.3 %

Procedure:
Naphthalene-1,5-diamine (3.14 g, 19.8 mmol), 1-bromooctane (25.25 g, 0.130 mol), potassium carbonate (11.79 g, 85.3 mmol), and potassium iodide (0.05 g, 0.30 mmol) was stirred in dry butanol (150 ml) and heated to 110° C. for 36 h. The reaction was quenched with water and extracted with ether three times. The combined organic phase was washed three times with water and evaporated to give black oil which was distilled under reduced pressure at 90° C. to yield a black tar. This was purified with flash chromatography using hexane as mobile phase to obtain colourless oil which crystallised to yield N1,N1,N5,N5-tetraoctylnaphthalene-1,5-diamine (2.3 g, 3.79 mmol) as white crystals. 1H-NMR (CDCl3, δ): 0.85 (t, 12H), 1.0-1.4 (m, 40H), 1.4-1.6 (m, 8H), 3.08 (t, 8H), 7.1 (d, 2H), 7.35 (t, 2H), 8.01 (d, 2H) MS MALDI-TOF (m/z): 606.574
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+].[Na+].[Cl-]>CS(C)=O>[C:27]([CH2:12][CH:13]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)#[N:28]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)c2ccsc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC#N)c1ccsc1
Temperature: 90 °C

Procedure:
To 2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)ethyl 4-methylbenzenesulfonate (E2) in DMSO was added NaCN, and the solution was heated to 90° C. for 2 hours. The reaction was cooled, poured into NaCl (sat), and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 25% EtOAc/Hexanes) gave pure tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([CH2:31][NH2:32])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:32][CH3:31])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
To a solution (5 mL) of 1-[(4-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg) in tetrahydrofuran was added benzylmethylamine (88 mg), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (329 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), 10% palladium carbon (50% water-containing product, 180 mg) and formic acid (0.027 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a colorless oil (yield 55 mg, 33%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](=[O:37])[NH:16][C:17]2[CH:18]=[C:19]3[C:35](=[O:36])[NH:34][N:33]=[CH:32][C:21]4=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[NH:23][C:24]([CH:25]=2)=[C:20]34)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[O:36]=[C:35]1[C:19]2[C:20]3[C:21](=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:23][C:24]=3[CH:25]=[C:17]([NH:16][C:15](=[O:37])[CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:18]=2)[CH:32]=[N:33][NH:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCNCC1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 91 %

Procedure:
Preparation of example 32 from the title compound of Example 30 (31 mg, 0.062 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (29 mg, 0.056 mmol) as a yellow powder in 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[C:15]2[N:14]([C:16](=[O:18])[CH3:17])[C:13](=[O:19])[N:12]([C:20](=[O:22])[CH3:21])[C:11]=2[CH2:10][S:9]1>C(OC(=O)C)(=O)C.[Pt]=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:15]2[CH:11]([N:12]([C:20](=[O:22])[CH3:21])[C:13](=[O:19])[N:14]2[C:16](=[O:18])[CH3:17])[CH2:10][S:9]1
Reactant: COC(=O)CCCCC1SCc2c1n(C(C)=O)c(=O)n2C(C)=O
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCCCC1SCC2C1N(C(C)=O)C(=O)N2C(C)=O
Reaction time: 6 h

Procedure:
In a 50 ml glass liner charged 12.8 mg of platinum oxide dampened with acetic anhydride. 417.7 mgs of N,N'-diacetyldehydrobiotin methyl ester high in the 1-isomer were added. The mixture was diluted to 50 ml with acetic anhydride. Hydrogenation was carried out at 550 psi of H2, 85° C., for 6 hours. After cooling the mixture was filtered through Celite removing the Pt metal. Stripping of solvent yielded a colorless oil. Analysis showed ~20% of starting material and 80% of reduction product high in the 1-isomer proportional to that in the starting material.
Reaction SMILES: Br[C:2]1[N:22](S(C2C=CC=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.ClCCl.[O:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[N:42]2)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:44]4[CH:43]=[N:42][N:41]([CH:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)[CH:45]=4)[NH:22][C:5]3=[N:6][CH:7]=2)[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C5CCOCC5)c4)cc3n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (15.0 mg, 29.8 μmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (1:1) (1.30 mg, 1.59 μmol), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.9 mg, 32.0 μmol), and potassium phosphate (13.5 mg, 63.6 μmol) in water (0.2 mL)/1,4-dioxane (0.40 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residues were dissolved in methanol (1 mL). Potassium carbonate (8.8 mg, 63.7 μmol) was added and the reaction mixture was then warmed up to 60° C. After 1 hour, the reaction mixture was cooled to ambient temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (2.5 mg) as its TFA salt. LCMS calculated for C24H28N5O3 (M+H)+: m/z=434.2. Found: 434.2.
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:15]([CH3:23])=[C:16]([N:20]=[C:21]=[S:22])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:23])=[C:16]([N:20]=[C:21]2[N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][S:22]2)[CH:17]=[CH:18][CH:19]=1
Reactant: ClCC[NH2+]Cc1ccccc1
Reactant: Cc1c(Cl)cccc1N=C=S
Agent: [Cl-]
Product: Cc1c(Cl)cccc1N=C1SCCN1Cc1ccccc1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1[CH:39]=[N:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[N:38]1[CH:39]=[CH:34][CH:35]=[C:36]([CH2:40][NH:41][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:33])[F:32])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)=[CH:31][CH:30]=2)[CH:37]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)O)cc4)ccc32)c1
Reactant: NCc1cccnc1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)NCc5cccnc5)cc4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 7 starting from 4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl)-amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid and picolamine (Aldrich Cat. No. A65409). LCMS (M+H)+: m/z=545.2.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.Cl.[CH3:19][N:20]([CH3:25])[CH2:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:19][N:20]([CH3:25])[CH2:21][C:22]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:23]
Reactant: CN(C)CC(=O)O
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CN(C)C)C2
Yield: 85.6 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while being cooled on ice. To the obtained mixture, a hydrochloric acid salt of N,N-dimethylglycine (1.45 g, 11 mmol), WSC.HCl (2.0 g, 11.0 mmol), and HOBT (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was subjected to distillation under reduced pressure. The resultant residue was recrystallized from ethanol--hexane. As a result, 2.7 g of the title compound was obtained as pale yellow powdery crystals (77.0%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C@H:13]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:14][C:15](OC)=[O:16].[OH-].[Na+]>O>[CH3:12][C@H:13]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24])[CH2:14][CH2:15][OH:16]
Reactant: COC(=O)C[C@H](C)CCO[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H](CCO)CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 8.5 g. (0.224 m) of lithium aluminum hydride in 250 ml. of diethyl ether under nitrogen was added 53.5 g. (0.206 m) of methyl 3-(R)-methyl-5-(t-butyldimethylsilyloxy)pentanoate in 125 ml. of ether. The reaction was stirred for one hour at 0° C. and was then treated dropwise with 8.4 g. of water, 8.4 ml. of a 15% sodium hydroxide solution and 25.2 ml. of water. The solids were filtered and the organic phase separated and washed with water, 2.5% hydrochloric acid and a brine solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give 46 g. of product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:16](Cl)(=O)[O:17]C(Cl)(Cl)Cl>O1CCOCC1>[F:15][C:3]1[C:2]([N:1]=[C:16]=[O:17])=[CH:14][C:6]2[N:7]([CH2:11][C:12]#[CH:13])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Solvent: C1COCCO1
Product: C#CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Yield: 119.5 %

Procedure:
To a solution consisting of 3.2 g of 5-amino-6-fluoro-3-propargyl-2-benzothiazolone and 50 g of dioxane were dropwise added 2.4 g of trichloromethyl chlorocarbonate at a temperature in the range of from 5° to 15° C. and the resulting mixture was heated under reflux for six hours. A residue was obtained by distilling off the low-boiling material from the mixture under reduced pressure, and it was dissolved in 150 ml of dried toluene and filtered. From the resulting filtrate toluene was distilled off to obtain 3.6 g of 6-fluoro-5-isocyanato-3-propargyl-2-benzothiazolone having a melting point in the range from 134° to 135° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=4)[CH:13]=3)[CH:9]=[CH:10][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O.CCN(CC)CC>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[N:20]=[C:21]([NH:25][C:32](=[O:35])[CH:33]=[CH2:34])[CH:22]=[CH:23][CH:24]=4)[CH:13]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc(Nc2cc(Oc3ccc4c(c3)OCCO4)ncn2)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(Nc2cc(Oc3ccc4c(c3)OCCO4)ncn2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)pyrimidin-4-yl)pyridine-2,6-diamine (0.080 g, 0.23 mmol) and potassium carbonate (0.065 g, 0.47 mmol) in NMP (0.8 mL) at 0° C. was added acryloyl chloride (0.026 g, 0.29 mmol) and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was added dropwise to a cold, stirring solution of 10% NaHCO3 and was stirred at 0° C. for 30 min. A white solid was isolated by filtration. The solid was washed with cold water and hexane and dissolved in a 2 mL of methanol/dichloromethane (1/1). This solution was concentrated under reduced pressure. The residue obtained was suspended in cold water (5 mL), Et3N was added to it and it was extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extract was washed with water (2 mL) and brine (2 mL), was dried over Na2SO4 and was concentrated under reduced pressure to obtain N-(6-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)pyrimidin-4-ylamino)pyridin-2-yl)acrylamide (I-95) as a light yellow solid. 1H NMR (DMSO-d6) δ ppm: 4.25 (s, 4H), 5.79 (dd, J=1.84 & 10.08 Hz, 1H), 6.30 (dd, J=1.84 & 16.96 Hz, 1H), 6.62-6.72 (m, 3H), 6.88 (d, J=8.72 Hz, 1H), 7.03 (d, J=7.84 Hz, 1H), 7.69 (t, J=7.96 Hz, 1H), 7.70 (d, J=7.84 Hz, 1H), 7.85 (s, 1H), 8.32 (d, J=0.4 Hz, 1H), 10.16 (s, 1H), 10.47 (s, 1H); LCMS: m/e 392.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:8]1([CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]1)[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:27])=[C:5]2[OH:34].O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[C:8]1([CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]1)[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[C:5]2[OH:34]
Reactant: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(C(=O)c3ccccc3)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(C(=O)c3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ester was treated with lithium hydroxide hydrate (0.025 g, 0.60 mmol) in THF (1.4 mL) and water (0.6 mL) and stirred at 25° C. for 30 minutes. The reaction was quenched with Dowex 50 (W×8) acidic resin (prewashed with MeOH) to pH<4.0 and filtered. The filtrate was concentrated and azeotroped with toluene (2×5 mL), to give the title compound (0.017 g). MS m/e=469.5 (M+H)+. Calculated for C24H21ClN2O6 468.11.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)Cl>CC#N.C(Cl)Cl>[C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([Cl:14])[CH:16]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCCC(=O)Nc1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(NC(=O)c2cccc(Cl)c2)c1

Procedure:
N-(3-Aminophenyl)butyramide (30 mg, 0.168 mmol), 3-chlorobenzoic acid (39.5 mg, 0.252 mmol), HOBt (28.4 mg, 0.185 mmol), and silica-supported DCC (from Silicycle Inc., 362 mg, 0.337 mmol) were added to a 13×100 mm test tube with stir bar. The tube was sealed with a rubber septum and dry DCM (3 mL) was added, then the reaction was stirred for 15 h. 50% CH3CN/DCM (4 mL) was then added, followed by silica-supported trimethylammonium carbonate (from Silicycle Inc., 534 mg, 0.337 mmol). The mixture was stirred for 1 h, then filtered through Celite and washed with 50% CH3CN/DCM (4 mL) and concentrated. The crude solid was redissolved with DCM and purified by column chromatography (EtOAc/hexanes gradient) to yield a white solid after precipitating from hexanes (39 mg, 73%). LRMS (ESI+) (M+H): 317.22.
Reaction SMILES: C=O.F[C:4](F)(F)C(O)=O.[N:10]1([C:16]2[N:21]=[CH:20][C:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[CH3:4][N:13]1[CH2:12][CH2:11][N:10]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C)CC4)nc3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Formaldehyde (37% aq., 0.212 mL, 2.61 mmol) was added to a suspension of ethyl 2-(6-piperazin-1-ylpyridin-3-yl)-1,3-benzothiazole-6-carboxylate trifluoroacetate (0.315 g, 0.65 mmol) in methanol (10 mL). Sodium cyanoborohydride (74 mg, 1.17 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The r.m. was then kept at −10° C. o.n. The formed solid was collected, washed with cold methanol and dried to give the title compound. The mother liquor was evaporated in vacuo and the residue was partitioned between DCM and sat. sodium hydrogencarbonate. The aqueous layer was extracted twice with DCM, dried (Na2SO4), filtered, and evaporated in vacuo, giving together with the filtrated solid the title compound (0.20 g) as a yellow solid. 1H NMR δ ppm 8.83 (d, 1 H) 8.73 (s, 1 H) 8.17 (dd, 1 H) 8.05 (s, 2 H) 7.01 (d, 1 H) 4.36 (q, 2 H) 3.70 (br. s., 4 H) 3.32 (s, 4 H) 2.29 (s, 3 H) 1.36 (t, 3 H); MS m/z (M+H) 383.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1OC)[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.[CH3:36][O:37]C1C=C2C(=CC=1OC)C(CNC)C2>>[ClH:1].[CH3:36][O:37][C:5]1[C:4]([O:3][CH3:2])=[CH:11][CH:10]=[C:9]2[C:6]=1[CH2:7][CH:8]2[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19]
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Reactant: CNCC1Cc2cc(OC)c(OC)cc21
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3c1ccc(OC)c3OC)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 10.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:18](=[O:31])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)C>[Pd].O1CCCC1>[CH3:1][O:2][CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:18](=[O:31])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC
Reaction time: 7.5 h
Yield: 95.1 %

Procedure:
Ethyl 2-methoxy-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]acrylate (150 mg, 0.354 mmol), 2.5 ml of ethanol and 2.5 ml of tetrahydrofuran were mixed, 10% palladium on activated carbon (30 mg) was added thereto, and normal pressure hydrogenation was conducted for 7.5 hours at room temperature. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 148 mg (98%) of the title compound as colorless crystals.