Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:17][C:4]2=[CH:5][C:6]3[NH:12][CH2:11][C:10]4=[N:13][CH:14]=[CH:15][N:9]4[CH2:8][C:7]=3[CH:16]=[C:3]2[O:2]1.[CH3:18][C:19]1[CH:36]=[CH:35][CH:34]=[CH:33][C:20]=1[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]1[O:17][C:4]2=[CH:5][C:6]3[N:12]([C:28]([C:27]4[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]5[CH:33]=[CH:34][CH:35]=[CH:36][C:19]=5[CH3:18])=[CH:32][CH:31]=4)=[O:29])[CH2:11][C:10]4=[N:13][CH:14]=[CH:15][N:9]4[CH2:8][C:7]=3[CH:16]=[C:3]2[O:2]1
Reactant: c1cn2c(n1)CNc1cc3c(cc1C2)OCO3
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1.0 mmol of 7,8-methylenedioxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[N:21]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+].Cl>C1COCC1.CO>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[N:14][N:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)Cn1nnc(-c2nnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1nnc(-c2nnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 25 °C

Procedure:
A solution of ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate (134 mg, 0.28 mmol) in THF/MeOH (2:1) (v/v) (4.6 mL) was treated with aqueous 1 N NaOH (1.5 mL). The reaction mixture was stirred at room temperature until TLC indicated disappearance of the starting material. The reaction mixture was poured into aqueous aqueous 0.5 N HCl, extracted with EtOAc, washed with brine. The organic layer was dried (Na2SO4) and filtered. Evaporation of the solvent was followed by trituration in a mixture of Et2O/heptane with stirring for 1 h at room temperature. After this time, the title compound was collected by filtration as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=4[F:26])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:21][C:20]=4[F:26])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(C#C[Si](C)(C)C)cc4F)n(C)c(=O)c(C)c32)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Under a nitrogen atmosphere, to N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 59 (14.5 g) obtained in Example 4-1 were added chloroform (145 ml), trimethylsilylacetylene 60 (4.99 ml) and triethylamine (13.1 ml). Copper(I) iodide (22 mg) and bis(triphenylphosphine)palladium(II)chloride (83 mg) were added, and the mixture was stirred at room temperature for 20 hrs. The mixture was concentrated under reduced pressure, activated carbon (435 mg) and methanol (435 ml) were added to the residue, and the mixture was stirred with heating at reflux for 2 hrs. Activated carbon was filtered off while it was hot, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=10:1→4:1) and toluene-acetone [5:1 (volume ratio), 87 ml] was added to the obtained crystals. The mixture was stirred at 80° C. for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 61 (12.9 g, yield 93%) as pale-yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1.[CH3:14][C:15](C)([O-])C.[K+].BrCC>CN(C=O)C>[CH2:14]([N:11]1[CH:12]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH:8]=[CH:9][C:10]1=[O:13])[CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: O=c1ccc(-c2cnccn2)c[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCn1cc(-c2cnccn2)ccc1=O
Reaction time: 0.75 h

Procedure:
A suspension of 5-(2-pyrazinyl)-2(1H)-pyridone (6.5 g) and 6.6 g of potassium t-butoxide in 250 ml of dry DMF is stirred with warming until all the solid is dissolved. The stirred solution is cooled in an ice bath and 4.6 ml of bromoethane are added when the temperature reaches 5° C. The ice bath is removed and stirring is continued for 45 minutes at which time 0.5 ml of additional bromoethane is added. Stirring is continued over the weekend. 10 g of sodium bisulfate in distilled H2O are added to the reaction mixture which is filtered. The filtrate is evaporated and the residue taken up in boiling isopropanol. The isopropanol solution is treating with decolorizing charcoal and filtered while hot. The filtrate is evaporated in vacuum to remove residual DMF, resulting in the formulation of a solid. The solid is recrystallized from acetonitrile with hot filtration. The starting material crystallizes out. The acetonitrile mother liquid is evaporated and the residue chromatographed on 100 g of silica gel. The column is eluted with ethyl acetate, toluene and finally with methanol in ethyl acetate. The early fractions are discarded and the latter fractions are combined and recrystallized from hot toluene/decane and air dried, resulting in the desired 1-ethyl-5-(2-pyrazinyl)-2-pyridone, M.P. 119.5°-120.7° C.
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:17]1[C:29]([OH:31])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[NH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([C:50]#[N:51])=[CH:42][CH:41]=1>CCOC(C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[C@H:17]1[C:29](=[O:31])[NH:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([C:50]#[N:51])=[CH:42][CH:41]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: N#Cc1ccc(N)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)Nc1ccc(C#N)c2ccccc12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A solution of isobutylchloroformate (0.75 ml, 5.8 mmol) in dry EtOAc (8.0 ml) was cooled to −20° C., treated dropwise with a mixture of 30B (2.0 g, 5.8 mmol) and N-methylmorpholine (0.64 ml, 5.8 mmol) in dry EtOAc (6.0 ml) over a period of 45 minutes. The mixture was stirred at −20° C. for 30 minutes, then treated dropwise over a period of 1.5 h with a solution of 4-aminonaphthalene carbonitrile (976 mg, 5.8 mmol) in dry EtOAc (35 ml). The reaction mixture was stirred at −20° C. for an additional 3.0 h, then at RT for 4 days after which it was partitioned between water (50 ml) and EtOAc (3×250 ml). Purification by flash chromatography provided the title compound as a dark pink foam (2.19 g, 76.3%). MS (ES): m/z 496 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:13]([NH:18][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCN
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccnc1NCCC(C)C
Temperature: 140 °C
Yield: 75.7 %

Procedure:
A mixture of ethyl 2-chloronicotinate (3.71 g, 20 mmol), isoamylamine (3.03 mL, 26 mmol) and triethylamine (3.62 mL, 26 mmol) was heated in a sealed tube at 140° C. for 8 hours, cooled to 25C, diluted with ethyl acetate and the mixture washed with water. The organic layer was extracted with 1N aqueous hydrochloric acid. The acidic aqueous layer was adjusted to pH 8.0 with saturated sodium bicarbonate solution then extracted with ethyl acetate (2 portions). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.58 g, 76%). MS (DCI/NH3) m/z 237 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.25 Hz, 6 H) 1.31 (t, J=6.99 Hz, 3 H) 1.47 (q, J=6.99 Hz, 2 H) 1.64 (m, 1 H) 3.47 (m, 2 H) 4.28 (q, J=6.99 Hz, 2 H) 6.59 (dd, J=7.72, 4.78 Hz, 1 H) 7.90 (t, J=5.15 Hz, 1 H) 8.07 (dd, J=7.91, 2.02 Hz, 1 H) 8.28 (dd, J=4.78, 1.84 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]#[C:17][CH2:16][S:15][CH2:14][C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][S:37]([CH3:36])(=[O:39])=[O:38])(=[O:39])=[O:38]
Reactant: Oc1ccccc1CCCCC#CCSCC#CCCCCc1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1CCCCC#CCSCC#CCCCCc1ccccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of 82 (0.2 g, 0.9 mmol) in 2 mL of anhydrous CH2Cl2 at 0° C. was added anhydrous pyridine (71 mg, 0.9 mmol) and methylsulfonyl chloride (0.1 g, 0.9 mmol) under argon (FIG. 2N). The solution was stirred at room temperature for 6 h. The reaction was carefully quenched with water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with water, dried (MgSO4), and concentrated in vacuo. Chromatography on silica gel (EtOAc:hexanes, 5:95) gave the desired methylsulfonyloxy derivative 124 as a colorless oil (0.22 g, 84%). 1H NMR (CDCl3) δ7.51-7.53 (dd, 1 H, J=7.6 Hz and 2.6 Hz, ArH), 7.40-7.42 (dd, 1 H, J=7.9 Hz and 2.8 Hz, ArH), 7.26-7.30 (m, 2 H, ArH), 3.66 (t, 2 H, J=1.3 Hz CH2), 3.24 (s, 3 H, CH3), 2.11-2.13 (m, 2 H, CH2), 1.26-1.41 (m, 4 H, CH2), 0.84-0.87 (t, 3 H, J=7.1 Hz, CH3); 13C NMR (CDCl3) δ147.63, 130.77, 129.18, 127.82, 127.59, 123.20, 84.74, 74.54, 38.50, 30.52, 21.97, 21.77, 18.37, 13.53.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=O)[CH:23]=[CH:24][C:25]=1[Cl:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][NH:12][C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CCN[C@@H]2CCCC[C@@H]2N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-cis-2-(1-pyrrolidinyl)cyclohexylamine (5 gm) was combined with pyridine (1.2 gm), chloroform (200 ml), 3,4-dichlorophenylacetic acid (9.15 gm), and dicyclohexylcarbodiimide (12.3 gm) and the mixture was stirred for 12 hr at room temperature. The mixture was filtered, the precipitate was washed with ether (100 ml) and the filtrate and ether wash were combined. The organic solution was diluted with ether (200 ml) and extracted with 10% citric acid in water (300 ml). The acid layer was washed with ether (2×200 ml), then treated with excess concentrated aqueous ammonia until basic. The resulting mixture was extracted with methylene chloride (2×200 ml) and the combined organic extracts were washed with water (2×50 ml) and concentrated on a rotary evaporator. The resulting white solid was combined with tetrahydrofuran (25 ml) and added dropwise to a solution of AlH3 in tetrahydrofuran (76.2 ml of a 0.665M solution) at room temperature. After the addition, the mixture was poured into 15% NaOH and the resulting mixture was extracted with ether (3×100 ml). The ether was removed on a rotary evaporator and the residue was dissolved in ethanol (100 ml). The ethanol was removed on a rotary evaporator and the residue was converted to the hydrogen bromide salt which was recrystallized from ethanol. Analytical data are reported in Table I.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2([CH2:25]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]2=[O:24])=[C:4]([OH:27])[CH:3]=1.ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[O:27][CH2:25][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]3=[O:24])[C:5]=2[CH:6]=1
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2ccccc21
Yield: 46 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl [3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 46% yield as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.31 (dt, 1H), 7.16 (dd, 1H), 7.08 (dt, 1H), 6.81-6.71 (m, 2H), 6.67 (dd, 1H), 4.98 (d, 1H), 4.74 (d, 1H), 4.64 (d, 1H), 4.37 (d, 4.24 (q, 7.1 Hz), 1.28 (t, 3H); MS (ES+) m/z 360.5 (M+1).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]>N.CO>[F:29][C:30]1[CH:31]=[C:32]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[CH3:36]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3-Fluoro-4-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.4 mg). MS m/z 361 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1>O>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:24]3[CH2:25][CH2:26][CH:22]([OH:21])[CH2:23]3)=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: OC1CCNC1
Solvent: O
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC(O)C3)nc21
Temperature: 170 °C

Procedure:
A suspension of the 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.14 g) in 3-hydroxypyrrolidine (0.29 g) in an open test tube was heated at 170° C. for 30 minutes. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed, dried, and evaporated. Chromatography over silica gel with ethyl acetate gave the title compound, which crystallized from ethyl acetate. Yield, 0.12 g, m.p. 131°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[CH:16]([O-])([O-])OCC>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH:16]=[N:15][N:14]=2)[N:13]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1ncc(-c2ccccc2Cl)nn1
Product: Clc1ccccc1-c1cnc2nncn2n1

Procedure:
A mixture of 4.45 g. of 6-(o-chlorophenyl)-3-hydrazino--1,2,4-triazine and 50 ml. of ethyl orthoformate is refluxed for 4 hours and then cooled, giving the desired product as yellow crystals, m.p. 145°-148° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.28 mL of triethylamine and 0.12 mL of benzoyl chloride were added to 3 mL of methylene chloride solution containing 0.31 g of tert-butyl 2-amino-4-(3-phenylpropyl)benzoate sequentially while ice-cooled and stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to obtain 0.48 g of tert-butyl 2-(benzamido)-4-(3-phenylpropyl)benzoate as while solid.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1)#[CH:2].[CH2:25]([N:32]=[N+:33]=[N-:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CO.[Cu]I>[CH2:25]([N:32]1[CH:2]=[C:1]([C:3]2[CH:24]=[CH:23][C:6]3[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[N:8][C:9]4[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=4[C:5]=3[CH:4]=2)[N:34]=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccc2c(NC(C)C(C)(C)C)nc3cc[nH]c(=O)c3c2c1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(-c3cn(Cc4ccccc4)nn3)ccc12)C(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
9-ethynyl-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.47 mmol) was dissolved in DMF/MeOH (2 mL) in a sealed tube. To the solution was added CuI (5.0 mg, 0.020 mmol) and Bn—N3 (310 mg, 2.4 mmol) under an argon atmosphere. The mixture was stirred at 100° C. for 8 h, then the resulting solution was filtered and purified by reverse phase HPLC to afford 9-(1-benzyl-1H-1,2,3-triazol-4-yl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 8.64 (m, 2H), 8.30 (d, J=8.4 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H), 7.40 (m, 5H), 6.93 (d, J=7.2 Hz, 1H), 5.70 (s, 2H), 4.46 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.09 (s, 9H). LRMS calculated for C27H28N6O [M+H]+, 453; found 454.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([Mg]Cl)[CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:7]([CH2:8][CH:9]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)[OH:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cl[Mg]c1cccc(Cl)c1
Reactant: O=CCc1cccnc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1cccnc1Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.4 %

Procedure:
To 2-(2-bromopyridin-3-yl)acetaldehyde (864 mg, 4.7 mmol) in THF (10 mL) at 0° C. was added (3-chlorophenyl)magnesium chloride (0.5M in THF, 14 mL, 7.04 mmol). The mixture was stirred at room temperature for 4 hours then treated with ammonium chloride (sat) at 0° C., extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave 2-(2-bromopyridin-3-yl)-1-(3-chlorophenyl)ethanol (490 mg, 35% yield) as white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[CH3:18].C(OC(C)(C)C)(C)(C)C.[K].O>CN(C)C=O>[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH3:18]
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cc(N)ccc1Br
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2ccc(C#N)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a mixture of 4-fluorobenzonitrile (12.61 g, 104 mmol) and 4-bromo-3-methylaniline (15.36 g, 82.56 mmol) in N,N-dimethylformamide (160 mL) on an ice water bath under a nitrogen balloon was added potassium tert-butyloxide (18.53 g, 165.12 mmol) portionwise. The reaction was stirred at room temperature overnight. Then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to get crude product. The crude was then recrystallized from ethyl acetate to give 4-(4-bromo-3-methylphenylamino)benzonitrile (5.675 g, 24%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[C:50]([NH2:61])[CH:51]=[N:52][C:53]=2[O:54][C@@H:55]([CH3:60])[C:56]([F:59])([F:58])[F:57])=[CH:44][CH:43]=1>CN(C=O)C>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:49]=[C:50]([NH:61][C:7]([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:9])[CH:51]=[N:52][C:53]=2[O:54][C@@H:55]([CH3:60])[C:56]([F:57])([F:58])[F:59])=[CH:46][CH:47]=1
Reactant: O=C(O)c1cccnn1
Reactant: C[C@H](Oc1ncc(N)cc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ncc(NC(=O)c2cccnn2)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Pyridazine-3-carboxylic acid (CAN 2164-61-6; 43.1 mg, 347 μmol) was suspended in DMF (1.0 mL). TBTU (112 mg, 347 μmol), ethyldiisopropylamine (102 mg, 131 μl, 789 μmol,) and 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (0.100 g, 316 μmol) were added and the reaction mixture was stirred at room temperature for 1 h. The rection mixture was extracted with ethyl acetate and 1M citric acid solution; the organic phase was dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 10% to 50% ethyl acetate in heptane) to give 0.11 g (83%) of the title compound as white solid; MS (EI) 423.1 (M+H)+.