Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][F:30])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][Mg]Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:39])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][F:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[S:14]2)[C@H:10]1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(CCF)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3aR,5S,6S,7R,7aR)-6,7-bis(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (400 mg, 0.73 mmol) in THF (20 mL) was added methylmagnesium chloride (1 mL, 3M in THF). After stirred for 3 hours at 0-5°C., the resulting solution was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 20% ethyl acetate in petroleum ether to give compound 73 as a yellow oil (0.37 g, 90%, diasteromers' ratio is 1:4). (ES, m/z) [M+H]+ 561.0; 1H NMR (300 MHz, CDCl3) δ 7.25-7.44 (m, 10H), 6.13-6.15 (d, J=6.9 Hz, 1H), 4.73-4.78 (m, 2H), 4.54-4.68 (m, 2H), 4.28-4.49 (m, 4H), 4.07-4.25 (m, 2H), 3.75-3.97 (m, 2H), 3.12-3.17 (m, 1H), 1.54 (s, 9H), 1.22-1.24 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Na].CC[O:16]CC>CO>[F:9][C:6]1[CH:5]=[C:4]([OH:16])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOCC
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1c(O)cc(F)cc1F

Procedure:
To a stirred solution of 2,3,4-trifluoronitrobenzene (5 g, 28.23 mmol) in dry methanol (70 ml) was added a solution of sodium (0.68, 29.46) in dry methanol (30 ml). The solution was stirred until all starting material was consumed (˜2 h). After concentration water was added and the solution was extracted with ether, dried over Na2SO4, filtered and concentrated to a yellow residue (4.65 g). To the solution of the yellow residue in dichloromethane (140 ml) was added boron tribromide (1M in dichloromethane, 40 ml) and stirred at room temperature overnight. Water was then added and the solution stirred for further 30 min. The organic phase was separated and the water phase was extracted with ether. The combined organic phase were dried over Na2SO4, filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and neutralized with 6M HCl and extracted with ether, dried over Na2SO4 and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with EtOAc:Heptan; 1:2 as eluent to give the desired product 2 g, 11.42 mmol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12]C2CCCCO2)[O:9][CH:10]=1.O.N>CO.Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][OH:12])[O:9][CH:10]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCl
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: O=c1cc(CO)occ1OCCCl
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.9 %

Procedure:
To a solution of 314 g of 5-(2-chloroethoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 630 mL of methanol, 6.3 mL of concentrated hydrochloric acid was added and the mixture was stirred for 6 hours at room temperature. To the reaction mixture, 13 mL of 28% ammonia water was added and the solvent was evaporated under reduced pressure to give 240 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-pyran-4-one (crude product) as a brown oily substance.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S@:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:8])=[CH:3][CH:2]=1.C([Mg]Br)(C)(C)C.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][C@H:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH:33]=[O:34].Cl>CCOCC.C1COCC1>[OH:34][CH:33]([CH2:32][CH:31]([O:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@H:9]([S@@:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)=[O:8])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: Cc1ccc([S@@](=O)CC(=O)OC(C)(C)C)cc1
Reactant: CCCCCCCCCCC[C@H](CC=O)OC1CCCCO1
Agent: CC(C)(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(CC(O)[C@H](C(=O)OC(C)(C)C)[S@](=O)c1ccc(C)cc1)OC1CCCCO1
Temperature: -78 °C
Yield: 61.3 %

Procedure:
(G)(a) 16.5 g of t-butyl [(S)-p-tolylsulfinyl]acetate were dissolved in a mixture of 600 ml of ether and 60 ml of THF and cooled to -78° C. 43 ml of t-butylmagnesium bromide were then added dropwise in such a manner that the temperature remained below -70° C. After stirring at -78° C. for 1 hour 13.4 g of (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-tetradecanal in 100 ml of THF were added dropwise. After 2 hours at -78° C. the reaction mixture was hydrolyzed with 2N hydrochloric acid and the solvent was evaporated off. The reaction mixture remaining behind was extracted with ether and the ethereal phase was dried and evaporated. After chromatography on silica gel there were obtained 14.9 g of t-butyl 3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]-hexadecanoate (67% yield). m.p. 97°-98° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[C:7]([C:8](=[S:26])[NH2:10])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 70 °C
Yield: 75.8 %

Procedure:
To a mixture of 5-bromo-2-(3-ethylureido)isonicotinamide (Intermediate 43, 1.25 g, 4.35 mmol) in THF (20 mL), was added Lawessons reagent (1.761 g, 4.35 mmol). The reaction mixture was then heated to 70° C. overnight. The solid that formed was collected by filtration and washed with THF to provide 1 g of desired product. MS (ESP): 304 (M+1) for C19H11BrN4OS
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Oc1cccc(O)c1
Product: Oc1cccc(OCc2cccc(F)c2)c1
Yield: 7 %

Procedure:
Prepared in analogy to example 8 from resorcinol and 3-fluoro-benzylbromide. Colorless oil. Yield=7%. MS: m/e=218.1 (M+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[Cl:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=1)=[C:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cc(Cl)ccc12
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccc(Cl)cc4c23)cc1)c1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 1,9-dichloro-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-aminophenyl)benzamide to provide 293. LC-MS (M+H=442, obsd.=442).
Reaction SMILES: [F:1][C:2]([P:8](Cl)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].C([SnH](CCCC)CCCC)CCC>BrCCCCCCBr>[F:7][C:2]([PH:8][C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])([F:1])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Agent: BrCCCCCCBr
Agent: CCCC[SnH](CCCC)CCCC
Product: FC(F)(F)C(F)(F)PC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.3 g (1.0 mmol) of bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, obtainable in accordance with Example 2, is condensed into a degassed solution of 0.61 g (2.0 mmol) of tributyltin hydride, (n-C4H9)3SnH, in 1,6-dibromohexane. The mixture is stirred at room temperature for one hour, and the volatile compounds are subsequently removed under dynamic vacuum conditions. Three cold traps are used: −30° C., −78° C. and −196° C. The cold trap at −196° C. contains a colourless liquid, bis(pentafluoroethyl)phosphine, (C2F5)2PH. The compound is stable at room temperature under inert-gas conditions.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:34]5[C:35]6[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:31]=[CH:32][CH:33]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc5ccccc45)cc32)n1)c1ccccc1
Yield: 87.9 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 415) (50 mg), 1-naphthyl boronic acid (22 mg), potassium carbonate (31 mg), and tetrakis(triphenylphosphine)palladium(0) (5 mg) were dissolved in degassed n-propanol (2.6 mL) and water (0.4 mL) and stirred at 80° C. under argon atmosphere for 15 hours. Upon cooling, the reaction mixture was filtered through Celite® (the ppt was washed with 10 mL of EtOAc) and evaporated. The residue was purified by preparative thin layer chromatoraphy eluted with 5% MeOH/CH2Cl2) giving 44 mg of the title compound. 1H NMR (500 MHz, CDCl3), δ 8.82 (br s, 1H), 8.38 (s, 1H), 7.97-7.75 (m, 4H), 7.54-7.29 (m, 9H), 7.19 (t, 1 H, J=7.5 Hz), 7.01 (d, 1H, J=Hz), 5.7 (s, 1H), 1.67 (d, 3H, J=7.0 Hz); Mass spectrum (ESI) 442.3 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:17])([CH3:16])[O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:18]([O:20][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](Cl)=[O:29])=[O:22])[CH3:19]>C1COCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:17])[CH3:16])[CH:10]=1)=[O:29])=[O:22])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of sodium hydride (0.25 g, 6.3 mmol) in anhydrous THF (20 mL) is added 3-(t-butyl-dimethyl-silanyloxy)-benzenethiol (1.3 g, 5.22 mmol) at RT. After 10 min, the title A compound, (R)-1-chlorocarbonyl-pyrrolidine-2-carboxylic acid ethyl ester (1.1 g, 5.22 mmol) is added and the reaction is stirred for 24 h. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield (R)-1-[3-(t-butyl-dimethyl-silanyloxy)-phenyl-sulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester as a clear oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.O=C1C(C2CCN(C(OC(C)(C)C)=O)CC2)CC2C(=CC=CC=2)N1>>[O:2]=[C:3]1[CH:4]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]2)[CH2:5][C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:12]1
Reactant: COC(=O)C(Cc1ccccc1[N+](=O)[O-])N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C2Cc3ccccc3NC2=O)CC1
Product: CC(C)(C)OC(=O)N1CCN(C2Cc3ccccc3NC2=O)CC1

Procedure:
tert-Butyl 4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperazine-1-carboxylate (770 mg, 2.0 mmol) was reacted in a manner analogous to the preparation of tert-butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxylate. Title compound was obtained as amber oil in quantitative yield. MS m/e (M+H)+=332.3.
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:44]=[CH:43][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([NH:34]C(OCC(Cl)(Cl)Cl)=O)[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[NH2:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:43]=[CH:44][C:9]([CH2:8][N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:2])[CH3:3])=[CH:10][CH:11]=3)[CH2:20][CH2:19]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(NC(=O)OCC(Cl)(Cl)Cl)ccc4c3)CC2)cc1)C(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(N)ccc4c3)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 1-(4-diisopropylaminomethylbenzoyl)-4-[6-(2,2, 2-trichloroethoxycarbonylamino)naphthalene-2-sulfonyl]piperazine (125 mg) in acetic acid (3 ml) was added zinc dust (1.0 g), and the solution was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was concentrated. The residue was dissolved in 1 N hydrochloric acid and the solution was made alkaline with 1 N sodium hydroxide solution. The precipitate was filtered, washed with water and dried to give pale purple solid of the title compound (92 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1cccc(O)c1
Product: Oc1cccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)c1

Procedure:
Intermediate 7 was coupled with 3-(2-amino-ethyl)-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 390. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.8 (m, 5H) 8.4 (d, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (d, 1H) 6.9 (m, 1H) 3.7 (m, 2H) 3.4 (m, 1H) 3.1 (m, 2H) 2.9 (m, 3H) 2.1 (m, 1H) 1.8 (m, 2H) 1.5 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:30](O)=[O:31])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][C@H:44]([CH3:46])[C@H:43]([N:47]2[CH:51]=[CH:50][N:49]=[N:48]2)[C@H:42]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO.O>[C:55]([O:54][C:53]([NH:52][C@H:42]1[C@@H:43]([N:47]2[CH:51]=[CH:50][N:49]=[N:48]2)[C@@H:44]([CH3:46])[CH2:45][N:40]([C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH:33][C:30]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:31])[CH2:41]1)=[O:59])([CH3:56])([CH3:57])[CH3:58]
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1=O
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
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: CO
Solvent: O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methyl-3-oxopiperazin-1-yl)quinoline-2-carboxylic acid (12.2 mg, 0.028 mmol), tert-butyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-3-yl]carbamate (10.0 mg, 0.027 mmol), HATU (33 mg, 0.087 mmol), in DMF (0.29 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with MeOH and H2O, filtered and the filtrate was purified by preparative LCMS (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to give the sub-title compound as a bright yellow powder (12 mg, 57%). LCMS calc. for C41H48N11O6 (M+H)+: m/z=790.4. Found: 790.3.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccccc2)nc1
Yield: 81 %

Procedure:
As described for example 84f, 6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (67 mg, 0.21 mmol) was converted, instead of [643-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (59 mg, 81%) which was obtained as an off white solid. MS: m/e=338.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:33]1([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:34][CH2:35]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c(OC)c1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-2,4-dimethoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9]O)[CH3:7].Cl>O>[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][P:1]([Cl:5])([Cl:3])=[O:2])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCC(CC)CO
Agent: Cl
Solvent: O
Product: CCCCC(CC)CP(=O)(Cl)Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 108.2 %

Procedure:
The synthesis of mono-2-ethylhexyldiphenyl phosphate: To 460 g of phosphorus oxychloride put into a 2 liter four-necked flask with cooling by iced water, while stirring, were added dropwise spending the period of an hour and ten minutes 402 g (3.09 M) of 2-ethylhexanol at the temperature of 10° C. And the mixture, with continued stirring, was heated slowly up to 50° C. spending 5 hours and a half, and was then kept at the same temperature for two hours, during which the inside of the flask was slowly decompressed, and finally decompressed down to 200 mmHg to remove the hydrochloric acid gas produced thereinside. When the hydrochloric acid gas was no longer produced, 750 g of mono-2-ethylhexylphosphoryldichloride were obtained (yield: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][S:8]([OH:11])(=O)=[O:9]>>[Cl:1][C:2]1[S:3][C:4]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:5][C:6]=1[S:8]([Cl:7])(=[O:11])=[O:9]
Reactant: Clc1cccs1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)c(Cl)s1
Temperature: 30 °C

Procedure:
2-Chlorothiophene (40 g) was added to stirred chlorosulphonic acid (400 ml) over a five minute period. The solution was then heated at 80°-90° C. for four hours, cooled to 30° C., and added to ice-water with stirring. The product was filtered off, washed with water and dried. The yield was 84 g.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.C([Li])CCC.CCCCCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[CH2:7]([C:5]1[S:6][C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:3][N:4]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ncc(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
To a solution of 5-bromo-2-isobutylthiazole (2.10 g, 9.54 mmol) in THF (20 mL) was added 1.6 M n-butyllithium in hexane solution (7.15 mL, 11.44 mmol) dropwise over 45 minutes at −78° C. The resulting solution was stirred at −78° C. for 10 minutes. Then the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.13 g, 11.44 mmol) was added to the above solution and stirred at −78° C. for 1.5 hours. The reaction was quenched with 1:1 saturated ammonium chloride and water and warmed up to close to room temperature. The resulting mixture was extracted with ethyl acetate, washed with water, brine and concentrated. The residue was subjected to flash column chromatography using 30% ethyl acetate/hexane to give a yellow oil (454 mg, 18% yield). 1H NMR, 400 MHz, CDCl3: δ 8.13 (s, 1 H), 2.95 (d, J=7.1 Hz, 2 H), 2.10-2.19 (m, 1 H), 1.36 (s, 12 H), 1.00 (d, J=6.6 Hz, 6 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:12][S:13]([NH2:16])(=[O:15])=[O:14].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][S:13]([CH3:12])(=[O:15])=[O:14])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
A mixture of 5,6-dichloronicotinic acid (800 mg, 4.16 mmol), methanesulfonamide (779 mg, 8.40 mmol), EDCI (1.56 g, 8.20 mmol), and DMAP (1.00 g, 8.20 mmol) in DCM (10 mL) was stirred at room temperature for 16 h. The reaction was quenched with water (5 mL) and the resulting mixture was concentrated. The residue was adjusted to pH around 5 by 1M HCl, extracted with DCM (30 mL×3), dried over Na2SO4. The organic layer was concentrated to afford 5,6-dichloro-N-(methylsulfonyl)nicotinamide (700 mg, 62% yield). LCMS (ESI) m/z: 269.0 [M+H]+.