Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5](Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:25]#[N:26])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=1.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[NH3:33]>ClC1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:25]2[N:26]=[C:25]([C:15]3[CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=[C:13]([Cl:12])[CH:14]=3)[N:33]=[C:5]([C:4]3[CH:3]=[C:2]([Br:1])[CH:10]=[C:9]([Br:11])[CH:8]=3)[N:26]=2)[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=1
Reactant: N#Cc1cc(Cl)cc(-c2ccccc2)c1
Reactant: N
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Clc1cc(-c2ccccc2)cc(-c2nc(-c3cc(Br)cc(Br)c3)nc(-c3cc(Cl)cc(-c4ccccc4)c3)n2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a stream of argon, a 300 ml three-necked flask equipped with a reflux condenser was charged with 3,5-dibromobenzoyl chloride (10.5 g) and 5-chlorobiphenyl-3-carbonitrile (15.0 g), and then chlorobenzene (100 mL) was added to the content. The thus-obtained solution was cooled to 0° C., and antimony pentachloride (10.5 g) was dropwise added thereto. The resultant mixture was stirred at room temperature for 20 minutes and then refluxed at 100° C. for 2.5 hours. The thus-obtained red-colored solution was cooled to −20° C., and an aqueous 28% ammonia solution (50 mL) was added to obtain a milky white liquid suspension. The suspension was stirred at room temperature for 3 hours, and then, gradually heated to 140° C. in an oil bath to distill away the organic solvent (80 mL) and water (28 mL). Chlorobenzene (100 mL×3) was added to the solution, and then the solution was filtered at 130° C. The filtrate was left to stand at room temperature, and then methanol (300 mL) was added thereto. The thus-obtained solid precipitate was collected by filtration, and washed with methanol twice (50 mL×2) and dried. Thus, 2.21 g of 4,6-bis(5-chlorobiphenyl-3-yl)-2-(3,5-dibromophenyl)-1,3,5-triazine was obtained as a white powder (yield: 9%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[CH3:26][O:27][C@H:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][C@H:28]([O:27][CH3:26])[CH3:32])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CO[C@H](C)CCN
Agent: Cl
Product: CO[C@H](C)CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-3-methoxybutan-1-amine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.32 Hz, 3H) 1.58-1.79 (m, 2H) 2.43 (s, 3H) 3.24 (s, 3H) 3.30-3.42 (m, 3H) 7.66 (dd, J=7.83, 1.26 Hz, 1H) 7.73 (s, 1H) 7.77 (br. s., 1H) 8.18 (br. s., 1H) 8.29-8.59 (m, 2H) 8.68 (t, J=5.31 Hz, 1H) 8.87-8.94 (m, 1H) 13.17 (br. s., 1H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCOCC1>[CH2:13]([O:12][C:3]([CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])=[O:11])[CH:14]=[CH2:15]
Reactant: CCOC(=O)CCCCBr
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
16.29 g (407.19 mmol) of sodium hydride are added in portions to a solution of 100 g (542.92 mmol) of diallyl malonate in 900 ml of dry dioxane at 5° C. After gas evolution ceases, the reaction mixture is warmed to 40° C. and stirred for 30 min. Then 56.76 g (271.46 mmol) of ethyl 5-bromovalerate in 100 ml of dry dioxane are added dropwise, and the mixture is stirred at 110° C. for 12 hours. After the reaction is complete, the mixture is cooled to room temperature and added to about 400 ml of ice-water. After neutralization with 1 N hydrochloric acid, the organic phase is separated off, and the aqueous phase is extracted three times with 250 ml of ethyl acetate each time. After the organic phases have been combined they are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. Subsequently excess diallyl malonate is removed by high vacuum distillation (boiling point: 57° C., 0.074 mbar). The resulting distillation residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). 73.92 g (236.65 mmol, 44% of theory) of a colorless liquid are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.Cl[C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[C:26]([Cl:33])[C:22]=1[C:23]([OH:25])=[O:24]>ClCCl>[Cl:33][C:26]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=2)[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CN(C)c1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CN(C)c1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 41.0 g of N,N-dimethyl-p-phenylenediamine, 100 ml of N,N-dimethylaniline, and 23.6 g of 2,6-dichloro-3-nitrobenzoic acid was heated for seven hours on a steam bath. The resulting cake was suspended in dichloromethane, filtered, and the solid washed with water. Recrystallization from DMF-ethanol provided 6-chloro-2[[4-(dimethylamino)phenyl]amino]-3-nitrobenzoic acid, mp 222°-223° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([SH:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:14]([O:16][C:17](=[O:27])[C:18](Br)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[C:18]([S:11][C:9]1[S:10][C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=2[N:8]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH3:15]
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(Sc1nc2ccc(OCC)cc2s1)c1ccccc1

Procedure:
2.3 g of Na is dissolved in 80 ml of ethanol; 21.1 g of 6-ethoxy-2-mercaptobenzothiazole is added and the mixture is stirred until solution takes place. 25.7 g of 2-bromo-2-phenylpropionic acid ethyl ester is then added and the mixture is stirred overnight at 20° and worked up in the customary manner to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester, m.p. 92°-94°.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C>[CH2:33]([O:20][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A solution of 30 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 400 ml of ethyl acetate was treated with 9.63 g of triethylamine and 16.31 g of benzyl bromide and then heated at reflux for 4 hours. On cooling the mixture to room temperature filtration and evaporation of the filtrate gave a residue which was purified by column chromatography on silica gel, using ethyl acetate/hexane (1:9) for the elution, to give 15.8 g of (E)-benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerate in the form of a clear oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[N:13]([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[N:13]([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:10]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: CCCn1ccc2c1CC(c1ccccc1)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCn1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 91.6 %

Procedure:
A mixture of 6-phenyl-1-propyl-4,5,6,7-tetrahydroindol-4-one (0.80 g), aminoguanidine hydrochloride (0.46 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water and washed with diethylether. To the mixture was added 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid in ethyl acetate (2 ml). The solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-1-propyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 9) (1.0 g) as colorless crystals of E/Z compounds.
Reaction SMILES: O.[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.C(OCC)C.S(Cl)([Cl:26])=O>>[ClH:26].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([Cl:26])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 9-acridinecarboxylic acid hydrate (10.0 g, 44.80 mmol) in 80 mL of thionyl chloride was refluxed at 100° C. under nitrogen for 2 hours, and then cooled to 25° C. The resulting solution was reduced to about half the original volume under reduced pressure, and then poured into 500 mL of anhydrous diethyl ether. The yellow precipitate was collected, washed with ether (3×100 mL), and dried under reduced pressure for 2 hours, to produce 12.95 g (~ 100% yield) of the product, which was used immediately for the next reaction.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:35]([CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCN1c1cccc(CBr)n1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc(N2CCCC2=O)n1
Reaction time: 18 h

Procedure:
A solution of 1-(6-bromomethylpyridin-2-yl)pyrrolidin-2-one (10.19 g, 39.94 mol) containing triphenylphosphine oxide impurity in DMF (80 mL) was treated with sodium azide (2.60 g, 39.94 mmol), stirred for 18 h and partitioned between EtOAc and water. The organic phase was separated and the aqueous phase re-extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil, contaminated with triphenylphosphine oxide; used in the next step without further purification; LC-MS retention time 2.19 min, (M+H)+ 218.
Reaction SMILES: N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[C:25]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[C:38]([OH:40])=O)([O:27]C(C)(C)C)=[O:26].C(N(CC)C(C)C)(C)C.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH2:58][N:59]2[C:67]3[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=3)[C:61]([NH:69][S:70]([C:73]3[S:74][C:75]([Cl:78])=[CH:76][CH:77]=3)(=[O:72])=[O:71])=[N:60]2)[CH:55]=[CH:56][CH:57]=1>CN(C)C=O>[CH:25]([OH:27])=[O:26].[Cl:78][C:75]1[S:74][C:73]([S:70]([NH:69][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][C:63]=3[OH:68])[N:59]([CH2:58][C:54]3[CH:53]=[C:52]([CH2:51][NH:50][C:38]([C@@H:33]4[CH2:34][O:35][CH2:36][CH2:37][NH:32]4)=[O:40])[CH:57]=[CH:56][CH:55]=3)[N:60]=2)(=[O:71])=[O:72])=[CH:77][CH:76]=1
Reactant: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1)[C@@H]1COCCN1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (77 mg, 0.124 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added at room temperature (S)-4-Boc-morpholine-3-carboxylic acid (26.2 mg, 0.113 mmol), followed by N,N-diisopropylethylamine 0.059 mL, 0.339 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-hydroxy-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (formate salt) (for a preparation see intermediate 15) ((56 mg, 0.113 mmol) in anhydrous N,N-dimethylformamide (2 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine:water (1:1), passed through a hydrophobic frit and evaporated in-vacuo. The was treated with hydrogen chloride (4M solution in 1,4-dioxane) (1 mL) and then added methanol (˜4 mL) until the reaction was in solution. Reaction stirred at room temperature for 2 hours. The reaction mixture was evaporated in-vacuo and the residue was dissolved in MeOH/DMSO (1 mL) and purified by Mass Directed AutoPreparative HPLC (MDAP) on (Sunfire C18 column Method A) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) using a method B over 25 min. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (13 mg, 19%). LCMS (System B) RT=1.63 min, ES+ve m/z 562/564 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].Br[CH:9]([CH3:13])[C:10](Cl)=[O:11].C(N(CC)CC)C>CC(C)=O>[CH3:13][CH:9]1[O:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[O:1][C:10]1=[O:11]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(Br)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1OC(=O)C(C)(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
5 g α-hydroxyisobutyric acid (48 mmol) and 5.15 mL 2-bromopropionyl chloride (50 mmol) were stirred at 75° C. under nitrogen for 12 h. 300 mL acetone and 14 mL anhydrous triethylamine (100 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium chloride salts, acetone was distilled off and the resulting mixture was dissolved in 450 mL ethyl acetate:hexane mixture (1:1). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from ethyl acetate:hexane mixture (1:10). 1H NMR (500 MHz, CDCl3): δ 5.1 (q, 1H), 1.705 (s, 6H), 1.69 (d, 3H). 13C NMR (500 MHz, CDCl3): δ 168.58, 166.64, 80.54, 72.90, 26.23, 25.27, 17.41. ELEM. ANAL. Calcd. for C7H10O4: C, 53.16; H, 6.33. Found: C, 52.86; H, 6.39. Yield: 46%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>O>[OH:9][CH2:8][CH2:10][NH:11][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Brc1cccnc1
Solvent: O
Product: OCCNc1cccnc1
Yield: 27.2 %

Procedure:
A mixture of 3-bromopyridine (25.10 g), ethanolamine (34.89 g) and cupric sulfate (2.90 g) in water (140 ml) was refluxed for 5 hours under stirring. The reaction mixture was washed with chloroform and the aqueous layer was separated out. To the aqueous solution was added an aqueous solution of potassium carbonate (22 g) and then the mixture was saturated with sodium chloride, and extracted with a mixed solvent of chloroform and ethanol (1:1). The extract was evaporated and the residue was subjected to column chromatography on silica gel (200 g) using a mixed solvent of chloroform and ethanol (5:1) as an eluent. The fractions containing an object compound were collected and evaporated to give 3-(2-hydroxyethyl)aminopyridine (5.96 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Li].CON(C)[C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26].[Cl-].[NH4+]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:25]([C:27]4[S:28][C:29]([Cl:32])=[CH:30][CH:31]=4)=[O:26])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1ccc(Cl)s1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)s3)ccc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (500 mg, 1.43 mmol) in THF (2 ml) was added n-buthyl lithium (2.5 M in hexane, 0.63 ml, 1.58 mmol) dropwise at −78° C. under an atmosphere of dry N2. After stirring at −78° C. for 30 minutes, a solution of 5-chloro-thiophene-2-carboxylic acid methoxy-methyl-amide (440 mg, 2.15 mmol) in THF (1 ml) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 15 hours. To the mixture was added a saturated aqueous solution of ammonium chloride at 0° C. THF was removed from the resulting heterogeneous solution. The aqueous mixture was extracted with chloroform (CHCl3). The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound of example 40A (273.5 mg, 46% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][C:38]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:45])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3oc(CNC(=O)c4cccnc4)cc3c21)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of the product from Step B (0.32 g, 0.847 mmol) in THF (20 mL) was added polymer supported di-isopropyl ethyl amine (3.86 mmol/g, 0.44 g, 1.69 mmol, 2 eq); this suspension was cooled (ice bath) and nicotinoyl chloride (0.15 g, 0.847 mmol) was added. The ice bath was removed and mixture was stirred for one hour, additional nicotinoyl chloride (50 mg) was added and the mixture was stirred at room temperature overnight. Triethylamine was added and after stirring for 10 min saturated aqueous sodium bicarbonate (150 mL) was added. This mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a solid (0.16 g, 39%): LC/MS m/z 484 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[O:8]1[CH:10]([CH2:11][CH3:12])[CH2:9]1.[CH3:13][Si](C)(C)N[Si](C)(C)C>Cl.ClCCl.CCOCC.[I-].[Zn+2].[I-]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][C@@H:10]([OH:8])[CH:11]([CH3:12])[CH3:13])(=[O:7])[OH:6]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCC1CO1
Reactant: NCCCP(O)O
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[C@H](O)CP(=O)(O)CCCN
Reaction time: 6 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 40° and treated with 0.64 g of anhydrous zinc iodide and 25 ml of (S)-(+)-1,2-exoxy-3-methyl-butane. An exothermic reaction occurs andthe epoxybutane refluxes. Reflux is continued for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at roomtemperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in some 2.0M aqueous hydrochloric acid and washedwith dichloromethane and ether. Removal of the water at 40° in vacuoaffords a brown solid which is purified by ion-exchange chromatography on DOWEX® 50 W×8 (14-40 mesh) to give 3-aminopropyl[2-(S)-hydroxy-3-methyl-butyl]phosphinic acid, m.p. 187°-189°, [α]D20 =-14.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[C:17]([OH:23])=[N:18][CH:19]=[CH:20][C:21]=1[OH:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([NH:15][C:16]3[C:17]([OH:23])=[N:18][CH:19]=[CH:20][C:21]=3[OH:22])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Reactant: Nc1c(O)ccnc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 2-chloroquinoline-8-carboxylic acid (0.42 g, 2.023 mmol), 3-aminopyridine-2,4-diol (Example 179b, 0.383 g, 3.03 mmol), HATU (1.154 g, 3.03 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.083 ml, 6.07 mmol) in DMF (2.023 ml) was stirred at RT for 16 h. The mixture was diluted with EtOAc (200 ml), added to a separatory funnel, and washed with water (3×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-chloro-N-(2,4-dihydroxypyridin-3-yl)quinoline-8-carboxamide (181b, 24% yield as a yellow solid). MS (ESI, pos. ion) m/z: 316.2 (M+1).