Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.BrCC1CCCCO1>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, (S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 144-146° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (dd, J=5.1, 0.6 Hz, 1H), 7.73 (ddd, J=7.8, 7.5, 1.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.22 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.17 (dd, J=7.4, 0.9 Hz, 1H), 7.03 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.29 (s, 1H), 5.26 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H), 4.15-4.11 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.4, 155.3, 148.6, 144.8, 142.0, 138.4, 138.2, 132.2, 129.0, 124.0, 123.7, 123.3, 122.3, 121.1, 111.8, 109.7, 99.5, 80.3, 64.6, 64.0, 58.2, 45.5; MS (ES+) m/z 387.0 (M+1).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[F:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1)=[O:30]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: OCc1cccc(Oc2ccccc2)n1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1cccc(Oc2ccccc2)n1

Procedure:
(6-Phenoxy-2-pyridyl)methyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate, MS m/e 462 (M+) is prepared using the procedure of Example 1 from (6-phenoxy-2-pyridyl)methanol and the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid.
Reaction SMILES: C1(O[C:8](=[NH:12])[NH:9][C:10]#[N:11])C=CC=CC=1.[NH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]=[C:20]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[C:30]([CH3:42])[CH:29]=1>C(O)(C)C>[C:8]([NH:9][C:10]([NH:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][N:21]=[C:20]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[C:30]([CH3:42])[CH:29]=1)=[NH:11])#[N:12]
Reactant: N#CNC(=N)Oc1ccccc1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCN)cc34)cc2C)cn1
Solvent: CC(C)O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=N)NC#N)cc34)cc2C)cn1
Temperature: 85 °C
Yield: 51.2 %

Procedure:
A mixture of 2-phenyl-N-cyano-isourea (50 mg, 0.31 mmol) and [6-(3-amino-prop-1-ynyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine (30 mg, 0.076 mmol) in isopropanol (3 mL) was heated at 85° C. in a sealed tube. The reaction was cooled to room temperature after 5 hours. Solvent was removed via rotovap. The residue was then purified by FCC to give the final product (18 mg, 51%) as a light yellow solid. MS ESI (+) m/z 463 (M+1) detected; 1H NMR (400 MHz, deuterated DMSO) □ 9.9 (s, 1H), 8.7 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 7.8 (m, 2H), 7.75 (m, 2H), 7.2 (m, 3H), 7.0 (m, 3H), 4.22 (m, 2H), 2.42 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:6])[C:3]([OH:5])=[O:4].CN(C)C(N(C)C)=N.C([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])(=O)C>CO>[F:21][C:20]([F:23])([F:22])[C:19]([NH:1][C@H:2]([CH3:6])[C:3]([OH:5])=[O:4])=[O:18]
Reactant: C[C@@H](N)C(=O)O
Reactant: CC(=O)OCC(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 5 h
Yield: 97.2 %

Procedure:
(R)-2-amino propionic acid (8.9 g, 0.1 mol) was dissolved in 100 ml of methanol, and 1,1,3,3-tetramethyl guanidine (15.6 g, 0.136 mol) was added. At room temperature, trifluoroethyl acetate (18.5 g, 0.13 mol) was added dropwise. After the completion of the addition, stirring is conducted to allow a reaction to proceed for 5 hours. Most solvent was removed by evaporation, and the residue was poured into 100 ml of water, acidified with 12 ml of concentrated hydrochloric acid, and extracted with ethyl acetate (3×60 ml). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and crystallized, washed with 160 ml of hexane, filtered, and dried, obtaining 18.0 g of product. The yield was 97.3%. MS: m/z 185.1
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([S:22][CH2:23][C:24](O)=[O:25])(=[O:21])[CH3:20].C(Cl)CCl.O>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:25])[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)SCC(=O)O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CC(=O)SCC(=O)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
2.94 g of 3-{3-(piperidinomethyl)phenoxy}propylamine was dissolved in 80 ml of dichloromethane, and stirred under cooling in an ice bath. 1.60 g of 2-(acetylthio)acetic acid and 2.26 g of EDC were added to this solution, and stirred at 0° C. for 30 minutes then at room temperature overnight. 100 ml of water and 50 ml of dichloromethane were added to the reaction solution, and extraction was carried out. The dichloromethane layer was washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography using methanol:dichloromethane=1:15 as developing solvent to obtain the colorless oily N-[3-{3-(piperidinomethyl)phenoxy}propyl]-2-(acetylthio)acetamide. Yield: 2.23 g.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][NH2:39]>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccccn1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCc3ccccn3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.95 mmol) in DMSO (5 mL) was added DIEA (245 mg, 1.90 mmol) and pyridin-2-ylmethanamine (124 mg, 1.15 mmol), and the reaction was stirred overnight at 90° C. in an oil bath. The solids were precipitated from water (50 mL), collected by filtration, washed with AcOEt (10 mL), and dried to afford methyl 2-(4-fluorophenyl)-3-[(pyridin-2-ylmethyl)amino]quinoxaline-6-carboxylate as a yellow solid (200 mg, 81%).
Reaction SMILES: [C:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].Cl[C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>>[C:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH:5]1[CH2:9][CH2:8][N:7]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]3[CH2:24][CH3:25])=[CH:16][C:15]=2[F:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CCCN(C(C)=O)C1CCNC1
Product: CCCN(C(C)=O)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1

Procedure:
3-(N-Acetyl-n-propylamino)pyrrolidine was allowed to react with 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in the same manner as described above and yield 7-[3-(N-acetyl-n-propylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Subsequent hydrolysis of this compound with hydrochloric acid gave 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-N-propylamino-1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride, m.p. about 270° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:28][CH3:29])=[C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:17]([N:18]=[CH:32][N:33]([CH3:35])[CH3:34])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:28][CH3:29])=[C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N=CN(C)C)cc2cc1OCCN1CCOCC1

Procedure:
A mixture of 0.69 g (1.7 mmol) of 3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic acid tert-butyl ester and 2.4 mL of N,N-dimethylformamide dimethyl acetal in 7.0 mL of toluene is heated under reflux for 1.5 hours. The solvent is evaporated and the residue is dried on high vacuum to yield 3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)naphthalene-2-carboxylic acid tert-butyl ester as purple white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15]([CH:19]([CH2:23][CH3:24])[C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[I:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[CH:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[CH2:23][CH3:24])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CCC(C(=O)O)c1cccc(F)c1
Reactant: NC(=O)c1cc(N)ccc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1cccc(F)c1

Procedure:
2-Iodo-5-[(2-(3-fluorophenyl)butanoyl)amino]benzamide is prepared from 5-amino-2-iodobenzamide and 2-(3-fluorophenyl)butanoic acid under standard amide coupling conditions with HATU.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:27][C:28]1[CH:47]=[CH:46][C:31]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.Cl>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]([CH2:27][C:28]3[CH:47]=[CH:46][C:31]([CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(-c2cc(/C=C/c3ccccc3)[nH]n2)cc1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of 5-[(E)-2-phenylvinyl]-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (330 mg, 1.05 mmol), sodium hydride (60% in oil, 40 mg, 1.00 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg, 1.00 mmol) was added to the reaction mixture at room temperature, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give the title compound (343 mg, yield 57%) as a yellow oil. MS: m/z 597 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:20](Br)[CH:21]=[CH2:22]>CO>[NH:1]([CH2:22][CH:21]=[CH2:20])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C=CCBr
Solvent: CO
Product: C=CCN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C)C(=O)OC

Procedure:
533 Mg. (2 meq.) of H-Tyr-D-Ala-OMe in 80 ml. of methanol with 400 mg. (4 meq.) of powdered KHCl3 and 484 mg. (4 meq.) of allyl bromide were refluxed 2.5 hours under nitrogen. The solution was evaporated to dryness and dried in vacuo over KOH. The desired product was purified by high performance liquid chromatography using reverse phase C-18 column and eluting with 0.1 molar NH4OAc ph 4.2 containing 23% acetonitrile. The mass spectrometric analysis of the isolated product confirms the presence of an N-allyl group on the dipeptide. TLC (S. C., BAW peptidechlorine spray) indicated the presence of one major component RF 0.65.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:36])[N:21]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH:26]([CH3:28])[CH3:27])=[O:18])=[C:11]([F:37])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:44]([NH2:48])(=[O:47])[CH2:45][CH3:46].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[F:37][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][C:44](=[O:47])[CH2:45][CH3:46])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:20](=[O:36])[N:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:28])[CH3:27])=[O:18]
Reactant: CC(C)Oc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: CCC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(OC(C)C)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Temperature: 90 °C
Yield: 49.3 %

Procedure:
N-(4-((2-Chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (180 mg, 0.340 mmol), Cs2CO3 (400 mg, 1.228 mmol), propionamide (200 mg, 2.74 mmol) and Xantphos (20 mg, 0.035 mmol) were combined in dioxane (10 mL), sparged with argon under sonication, treated with Pd2(dba)3 (15 mg, 0.016 mmol) and heated to 90° C. overnight. The solids were collected by filtration and washed with DCM and MeCN. The filtrate was evaporated and the residue purified by silica gel chromatography (0-100% EtOAc/DCM) to provide N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (95 mg, 49.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1 H), 10.52 (s, 1 H), 8.30 (dd, J=12.6, 7.2 Hz, 1 H), 8.18 (d, J=5.7 Hz, 1 H), 7.87 (d, J=7.9 Hz, 1 H), 7.68 (d, J=2.4 Hz, 1 H), 7.51-7.48 (m, 3 H), 7.35 (t, J=8.7 Hz, 2 H), 6.72 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=8.0 Hz, 1 H); 4.85 (m, 1 H), 2.34 (q, J=7.5 Hz, 2 H), 1.31 (d, J=6.0 Hz, 6 H), 0.99 (t, J=7.5 Hz, 3 H); MS (ESI) m/z: 567.1 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31](Cl)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: OCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCCCN2CCCCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-piperidin-1-yl-propan-1-ol (0.85 mmol, 121 mg) in THF at room temperature, NaH (1.2 mmol, 29 mg) was added and stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.42 mmol, 150 mg) was added. The resulting mixture was stirred at 50-55° C. over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 4-(4-Benzyloxy-phenyl)-3-butyl-6-(3-piperidin-1-yl-propoxy)-pyridazine.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:48][O:49][C:50](=[O:56])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55]>[Cl-].[Na+].O.CN(C=O)C>[CH3:48][O:49][C:50](=[O:56])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:15](=[O:16])[CH:14]=[C:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Reactant: COC(=O)CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.9 %

Procedure:
2-(9H-fluoren-9-ylidene)acetic acid (222 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 5-aminovaleric acid methyl ester hydrochloride (202 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (278 mg, 68% yield) as a white solid. LC-MS (m/z) 336 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:28]O)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:28][C:6]1[CH:7]=[CH:8][C:9]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:21]2)[N:13]=3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reaction time: 1 h

Procedure:
To a nearly clear solution of (3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol (0.394 g, 0.977 mmol) and triphenyl phosphine (0.294 mL, 1.27 mmol) in 10 mL DCM at 0° C. was added carbon tetrabromide (0.114 mL, 1.17 mmol) in one portion. The reaction mixture was allowed to stir 1 h, then was treated with 3.5 g silica gel and dried. Purification by silica gel chromatography, 40 g, 0-30% EA/hexanes gave 2-(4-(bromomethyl)-2-nitrophenyl)-5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine as an orange-yellow solid. MS (ESI) m/z: Calculated: 467.0; Observed: 467.6 (M++1).
Reaction SMILES: [C:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:35])[NH:19][C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH3:34])[CH:25]=3)=[N:21]2)=[C:16]([CH3:36])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH2:33]([O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][C:20]1[NH:19][C:18](=[O:35])[C:17]2=[C:16]([CH3:36])[N:15]=[C:14]([CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:22]2[N:21]=1)[CH3:34]
Reactant: CCOc1cc(Cc2nn3c(C(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1cc(Cc2nn3c(C(CCCc4ccccc4)C(C)O)nc(C)c3c(=O)[nH]2)ccc1OC

Procedure:
58 mg (0.12 mmol) of 7-(1-acetyl-4-phenylbutyl)-2-(3-ethoxy-4-methoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one are reacted analogously to Example 12 with 5 mg (0.12 mmol) of sodium borohydride to give 2-(3-ethoxy-4-methoxybenzyl)-7-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-methylimidazo[5,1-f]-[1,2,4]triazin-4(3H)-one.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:42]=[CH:41][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:41]=[CH:42][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1OC
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1OC

Procedure:
4-{4-[5-(3,4-Dimethoxy-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3,4-dimethoxy-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C25H26N4O5 [M+H]+: 463.1976. Found: 463.1976.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14](OC([O-])=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>O1CCOCC1.O>[C:17]([O:16][C:14]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of piperazine-2-carboxylic acid dihydrochloride in dioxan (1000 ml) and water (500 ml), at 10–15° C., was treated with aqueous sodium hydroxide solution (50%) over 15 minutes to adjust the pH to 9.1. This mixture was then treated portionwise (0.1 equivalent portions) with tert-butyl dicarbonate (114.6 g) over a period of 1 hour whilst maintaining the temperature at 5° C. and the pH around 8.8. After stirring at room temperature overnight the reaction mixture was cooled to 10° C., then the pH of the mixture was adjusted to 2 by the addition of hydrochloric acid (37%) and then the mixture was concentrated at 40° C. under reduced pressure. The resulting solid was treated with methanol (1500 ml) and this mixture was heated at reflux temperature and then filtered to remove the insoluble inorganics. The filtrate was evaporated to give the title compound (126 g) as an off white solid. MS: 231 [MH]+.