Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:50]([O:52][C:53]([NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:54])[CH3:51]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH:50]([O:52][C:53](=[O:54])[NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[O:58])[CH3:51])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)OC(=O)NCC(=O)OCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(=O)NCC(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a solution of 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (215 mg, 0.349 mmol) in dimethylformamide (22 mL) was added cesium carbonate (2.15 g, 6.6 mmol). After stirring for 10 min, a solution of the freshly made benzyl 2-((1-chloroethoxy)carbonylamino)acetate (2.77 g crude, ˜5.55 mmol) in dimethylformamide (5 mL) was added. The reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was taken up in ethyl acetate, washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 1-(2-(benzyloxy)-2-oxoethylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (191 mg, 64% yield). LCMS (ES+) m/z calcd. for C43H43Cl2F2N4O8 [(M+H)+]: 851, found: 851.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[S:20][CH2:21][C@@H:22]([C:24](O)=[O:25])[N:23]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][N:29](C)[C:30](C1OC(C2C=CC=CC=2)=CC=1)=O>>[CH3:27][O:28][N:29]([CH3:30])[C:24]([C@@H:22]1[CH2:21][S:20][C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=[CH:12]3)=[N:23]1)=[O:25]
Reactant: O=C(O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)o1
Product: CON(C)C(=O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Yield: 57.1 %

Procedure:
(R)—N-methoxy-N-methyl-2-(1-(phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxamide (65a) was prepared from 64a with the same method as used for 38d. 57.1% yield. 1H NMR (500 MHz, CDCl3) δ 7.92 (m, 2H), 7.77 (m, 3H), 7.51 (d, 1H, J=3.0 Hz), 7.46 (t, 1H), 7.35 (t, 1H), 6.61 (d, 1H), 5.58 (br, t, 1H) 3.82 (s, 3H), 3.73 (t, 1H), 3.43 (m, 1H), 3.21 (s, 3H). MS (ESI) m/z 452.1 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]CCCC.[CH3:21][C:22]([CH:24]([CH3:26])[CH3:25])=O.OS(O)(=O)=O>C1COCC1>[CH:24]([C:22]1([CH3:21])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]2[C:2]1=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:26])[CH3:25]
Reactant: CN(c1ccccc1)c1ccccc1Br
Reactant: CC(=O)C(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C1(C)c2ccccc2N(C)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Isopropyl methyl ketone (0.361 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.62 g (60%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.51 (s, 3H), 1.64 (s, 3H), 1.70 (s, 3H), 3.04 (s, 3H), 6.64 (m, 3H), 7.12 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 21.5, 22.2, 23.8, 31.8, 39.0, 114.6, 117.4, 120.6, 121.4, 125.1, 127.4, 127.8, 128.0, 128.7, 129.3, 133.6, 140.0, 141.1, 147.2, 149.5. HRMS (ESI) calc for C18H21N [M+H]+ 252.1747, found 252.1742. IR (KBr plate) 692 (m), 747 (s), 1137 (m), 1342 (m), 1443 (m), 1486 (s), 1499 (s), 1591 (s), 1601 (s), 2911 (m), 2984 (m) cm−1.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18]1([CH3:29])[CH:23]=[CH:22][C:21]([S:24](C#N)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:29][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:12]2[N:11]3[C:7](=[N:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=43)[S:6][N:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2nsc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (10.0 g, 40.4 mmole) and p-toluenesulfonyl cyanide (14.7 g, 81.0 mmole) in 120 mL of dichloromethane was stirred at room temperature for 20 h. The precipitate was filtered and washed with dichloromethane to yield 12.2 g (91%) of 3-(4-methylphenyl-sulfonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as white powder: mp 231-234 ° C.; 1H NMR (CDCl3) δ 8.53 (d, 1H), 8.04 (d, 2H), 7.82 (d, 1H), 7.56-7.44 (m, 4H), 2.53 (s, 3H) ppm; 13C NMR (CDCl3) δ 163.72, 150.38, 147.97, 147.54, 132.48, 130.30(2C), 129.97(2C), 128.49, 126.14, 123.06, 119.70, 114.67, 21.93 ppm; IR (KBr) ν 1592, 1525, 1444, 1337, 1151, 1081, 735 cm-1 ; HRMS calcd for C15H11N3O2S2 : 329.0293, found: 329.0300. Anal. Calcd for C15H11N3O2S2 : C, 54.70; H, 3.37; N, 12.76. Found: C, 54.29; H, 3.14; N, 14.59.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH2:8][N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[S:10]([C:13]1SC=CC=1)(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].S1C=CC=C1S(Cl)(=O)=O.CS(Cl)(=O)=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH2:8][N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[S:10]([CH3:13])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CN(c2cccnc2)S(=O)(=O)c2cccs2)cc(C(C)(C)C)c1O
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)(Cl)c1cccs1
Product: CC(C)(C)c1cc(CN(c2cccnc2)S(C)(=O)=O)cc(C(C)(C)C)c1O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 7, except the 2-thiophene sulfonyl chloride was replaced with methane sulfonyl chloride. Mp 133—134° C.; MS+1=391.1.
Reaction SMILES: [CH2-]C(C)=[O:3].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[CH2:22]1[CH2:27][CH2:26][CH:25]([N:28]=[C:29]=[N:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:24][CH2:23]1>CC(C)=O.C1COCC1>[C:29]([NH:28][CH:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:3]
Reactant: [CH2-]C(C)=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of freshly prepared acetonide-protected amino acid (0.2 mmol, 1 equiv) in acetone (1.5 mL) was added 3 mL of THF, N-methylmorpholine (0.22 mmol, 1.1 equiv), 1-hydroxybenzotriazole (0.44 mmol, 2.2 equiv), and hexapeptide amine (0.22 mmol, 1.1 equiv). The resultant mixture was cooled to 0° C. and DCC (0.22 mmol, 1.1 equiv) was added. The mixture was allowed to warm up to room temperature and stirred under N2 for 20 h, after which time the precipitated dicyclohexylurea (DCU) was removed by filtration and washed with small portion of CH2Cl2. The combined filtrate was washed with saturated NaHCO3 solution and dried over MgSO4. Concentration in vacuo and dissolution of the residue in EtOAc yielded more DCU. The residue remaining after a second filtration and concentration in vacuo was purified by chromatography with 10-40% acetone in freshly distilled n-hexane to give the N,O-Isopropylidene-protected heptapeptide 1-7 (SEQ ID NO:10).
Reaction SMILES: [CH3:1][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N+:19]#[C-:20]>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]=[CH:20][N:2]([CH3:1])[CH:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: [C-]#[N+]c1ccc(C)cc1C
Reactant: CNC=Nc1ccccn1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=CN(C)C=Nc2ccccn2)c(C)c1
Yield: 20.5 %

Procedure:
A mixture of N-methyl-N'-(2-pyridyl)-formamidine (2.5 g, 0.0185 m), 2,4-dimethylphenylisocyanide (2.4 g, 0.0185 m), cuprous oxide (trace amount) and dry toluene (60 ml) was heated on a steam bath with occasional agitation for 4 hours. The reaction mixture was then cooled, filtered through "Hyflo" (diatomaceous earth) and alumina, and the toluene filtrate evaporated to dryness in vacuo to yield a viscous oil. The oil was triturated with 60°-80° petroleum ether to yield a white solid. Crystallisation of this solid from ether/60°-80° petroleum ether yielded the product, 5-(2,4-dimethylphenyl)-3-methyl-1-(2-pyridyl)-1,3,5-triazapenta-1,4-diene, (1.0 g) m.p. 100°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CC[N:14](C(C)C)C(C)C>>[NH2:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncnc2ccccc12
Product: Nc1ncnc2ccccc12

Procedure:
4-Chloro quinazoline derivative 3a was reacted with the primary amine 2d in the presence of Hunig's base to provide the 4-amino quinazoline intermediate 3b. Ammonolysis of the ester group with 7N ammonia/methanol solution afforded carboxamide 3c. When R4 is a protecting Nosyl group, deprotection with cesium carbonate in the presence of thiophenol provides 3d.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.C([O:53][C:54](=[O:75])[C@H:55]([OH:74])[CH2:56][N:57]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=2[F:73])=[CH:62][CH:61]=1)[NH2:58])C.CCO.[Li+].[OH-].O>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:58][N:57]([CH2:56][C@@H:55]([OH:74])[C:54]([OH:75])=[O:53])[CH2:59][C:60]2[CH:61]=[CH:62][C:63]([C:66]3[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=3[F:73])=[CH:64][CH:65]=2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (69.3 mg, 450 μmol) and HCTU (186 mg, 450 μmol) were combined in DMF (1.9 mL, 24.5 mmol), and stirred at room temperature. After 15 minutes, DIPEA (214 μL, 1.2 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (150 mg, 0.4 mmol) were added. The mixture was stirred for 30 minutes at room temperature, then evaporated under reduced pressure. The residue was dissolved in EtOH (1.4 mL, 24.5 mmol). A solution of 1.0 M LiOH in water (2.0 mL, 2.0 mmol) was added, and the resulting mixture was stirred at 40° C. for 3 hours. The solvent was removed under pressure and the residue was purified by preparative HPLC to yield the title compound (110 mg, purity 100%) as a TFA salt. MS m/z [M+H]+ calc'd for C22H20ClFN4O5, 475.11. found 475.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[CH2:13][O:12][CH2:11][O:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:14].[OH-].[Na+].[ClH:17].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][Cl:26])=[N:23][CH:24]=1>O>[ClH:26].[ClH:17].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][S:14][C:2]2[NH:1][C:5]3[CH:6]=[C:7]4[CH2:13][O:12][CH2:11][O:10][C:8]4=[CH:9][C:4]=3[N:3]=2)=[N:23][CH:24]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: Sc1nc2cc3c(cc2[nH]1)COCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)COCO4)nc1
Reaction time: 0.5 h

Procedure:
To 3.7 g of 1,8-dihydro-m-dioxino(4,5-f)benzimidazole-2-thiol, suspended in 60 ml of alcohol, were added dropwise while stirring 1.5 g of sodium hydroxide in 30 ml of water and, after 30 minutes, there were added 3.4 g of 5-methyl-2-chloromethylpyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. This mixture was washed first with 3N sodium hydroxide, then neutral with water, dried over sodium sulfate and evaporated in vacuo. The crude porduct was dissolved while heating in a small amount of methanol and treated with 25 ml of 5N hydrochloric acid in ethylacetate. There was obtained 1,8-dihydro-2-[[(5-methyl-2-pyridyl)methyl]thio]-m-dioxino(4,5-f)benzimidazole dihydrochloride of melting point 153°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[N:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:37])=[O:36])[CH:34]=1.O>CS(C)=O.C(OCC)(=O)C>[Cl:28][C:29]1[C:30]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)=[CH:4][C:3]=2[C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:36])=[O:37])[CH:34]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: N#Cc1cccc(-c2ccc(O)c(-c3ccnnc3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C#N)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
4′-Hydroxy-3′-(pyridazin-4-yl)biphenyl-3-carbonitrile (Preparation 119, 330 mg, 1.21 mmol) and potassium carbonate (334 mg, 2.42 mmol) were dissolved in dimethylsulfoxide (7 mL). Then 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 558 mg, 1.21 mmol) was added and the reaction was stirred at room temperature for 2 hours. Water (15 mL) and ethyl acetate (25 mL) were added and the two layers were separated. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10% dichloromethane in ethyl acetate to give the title compound (561 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37]>Cl.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(N2CCOCC2)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccnc(N2CCOCC2)c1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
4-Chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide from step 2 was dissolved in a mixture of 4 M HCl in dioxane (8 mL) and water (2 mL), heated to 85° C. for 2 h. The solvent was evaporated and the residue was purified with HPLC to give 4-chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. MS m/z: 561 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][C:17]2[C:18]([CH3:29])=[N:19][NH:20][C:21]=2[CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:15]=1)[C:11]#[N:12]>ClCCl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][C:17]2[C:18]([CH3:29])=[N:19][NH:20][C:21]=2[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:4](=[O:6])[CH2:3][O:2][CH3:1])[CH2:27][CH2:28]2)[CH:15]=1)[C:11]#[N:12]
Reactant: COCC(=O)O
Reactant: Cc1n[nH]c(CN2CCNCC2)c1Oc1cc(Cl)cc(C#N)c1
Solvent: ClCCl
Product: COCC(=O)N1CCN(Cc2[nH]nc(C)c2Oc2cc(Cl)cc(C#N)c2)CC1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
N-Benzyl-N-cyclohexylcarbodiimide polymer bound (624 mg of 1.3 mmol/g, 0.480 mmol) was added in one portion to a stirred solution of methoxyacetic acid (37 μL, 0.480 mmol) and the amine of Example 78 (80 mg, 0.240 mmol) in dichloromethane (5 ml) at room temperature under nitrogen. The reaction was stirred for 1 hour and the polymer bound reagent was removed by filtration. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (45 mg) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccco1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccco3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to furan-2-boronic acid (37 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]1[C:12]([Cl:13])=[N:11][C:9]([Cl:10])=[N:8][C:6]=1Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:10][C:9]1[N:11]=[C:12]([Cl:13])[N:5]=[C:6]([NH:3][CH2:2][CH2:1][NH:4][C:6]2[N:5]=[C:12]([Cl:13])[N:11]=[C:9]([Cl:10])[N:8]=2)[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(NCCNc2nc(Cl)nc(Cl)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 15 g (0.25 mole) of ethylenediamine in 125 ml of cold acetone is added dropwise, at 0° to 5° C., to 92.2 g (0.5 mole) of cyanuric chloride, dissolved in 500 ml of acetone. The mixture is subsequently stirred for 30 minutes and a solution of 20 g (0.5 mole) of NaOH in 125 ml of water is then slowly added at 0° to 5° C. After stirring the mixture at the same temperature for four hours, it is diluted with 500 ml of ice-water and the solid is filtered off. The desired compound is obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33]CC)[O:30]CC)=[CH:26][C:4]=2[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[P:29](=[O:30])([OH:33])[OH:36])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOP(=O)(/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(/C=C/P(=O)(O)O)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonate (3-1) (1.0 equiv.) in DCM (0.095 M) at 0° C. was added TMSBr (10 equiv.). The reaction was warmed to room temperature over 2 hours, and then quenched with small amounts of MeOH. The DCM was removed by evaporation, and then added DMSO/water. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give the (E)-2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonic acid (10) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.76 (s, 1H), 9.33 (s, 1H), 9.03 (s, 1H), 8.82 (s, 1H), 8.60 (d, 1H, J=8.4 Hz), 7.87 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.31 (dd, 1H, J=17.6, 21.6 Hz), 7.03 (d, 1H, J=8.4 Hz), 6.69 (m, 2H), 6.61 (dd, 1H, J=2.8, 8.4 Hz), 3.64 (s, 3H), 3.14-3.06 (m, 2H), 2.97-2.91 (m, 2H), 2.23 (s, 3H). LRMS [M+H]=450.2
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].F[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]>C1COCC1>[N+:16]([C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[NH:1][CH2:2][CH2:3][OH:4])([O-:18])=[O:17]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
To a stirred solution of 2-aminoethanol (5 ml, 150 mmol) in THF (20 ml), 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (6.9 ml, 50 mmol) was added slowly at 0° C. After the completion of the addition, the reaction mixture was stirred at RT for 24 hrs. THF was evaporated using a rotary evaporator and the residue was extracted using water and ethyl acetate. Ethyl acetate was washed with more water, dried and evaporated to give crystalline 2-aminoethanol derivative (10.0 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13]C(=O)C)[CH2:7]2.[ClH:17]>>[ClH:17].[ClH:17].[NH2:13][CH:8]1[CH2:7][C:6]2[C:11](=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=2)[NH:10][C:9]1=[O:12]
Reactant: CC(=O)NC1Cc2cccc(N)c2NC1=O
Agent: Cl
Product: Nc1cccc2c1NC(=O)C(N)C2
Temperature: 110 °C

Procedure:
N-(8-Amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (8.4 g) was added to concentrated hydrochloric acid (84 mL), and the mixture was heated at 110° C. for three hours while being stirred, followed by stirring under cooling on ice. The formed precipitates were recovered through filtration, and the thus-obtained solid was washed with ethanol, followed by drying, whereby the title compound (9.17 g) was yielded.