Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+]>C(O)C.O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:21])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CCCCCCSc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCS(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 7-(4-chlorophenylsulfanyl)-heptanoic acid ethyl ester (1.6 g, 5.3 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (1.1 g, 5.3 mmol) in distilled water (10 mL). The mixture was heated at reflux for 1 hour. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL), then with brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:1 ethyl acetate:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (1.2 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].C[N:13](C=O)C>S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:13])=[O:6]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C)cc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
3,5-Dimethylbenzoic acid (50 g, 0.33 M, Aldrich) was suspended in thionyl chloride (150 mL) and DMF (0.5 mL) was added. The mixture was then refluxed for 2.5 hr. Excess thionyl chloride was evaporated in vacuo and the residue was added dropwise to ammonium hydroxide solution (ACS, 250 ml) cooled in an ice bath. The mixture was stirred for further 30 min. The white precipitate was then filtered, washed with water several times, and dried by standing on air. The crude product was dissolved in MC, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to afford 42 g (85%) of 3,5-dimethylbenzamide as a white solid. m.p. 148-149° C. 1H NMR (200 MHz, CDCl3) δ 2.35 (6H, s), 6.01 (2H, br. s), 7.15 (1H, s), 7.42 (2H, s).
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>CCO>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[N:11]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C(O)CCCS
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCSc1cccc(Br)n1
Yield: 85.8 %

Procedure:
A mixture of sodium (1.84 g.), EtOH (100 ml.) and 4-mercaptobutyric acid (5.28 g.) was heated to reflux and then treated with 2,6-dibromopyridine (9.5 g.), and the mixture heated under reflux for 18 hours and then evaporated to dryness. The residue was partitioned between water and ether and the aqueous phase was acidified with HOAc and extracted with ether. The ether extract was dried and evaporated to dryness to give 4-(2-bromopyrid-6-ylthio)butyric acid (9.5 g.), m.p. 72°-74°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
6-Chloropyridin-3-ol (30.00 g, 231.6 mmol), 1-(bromomethyl)benzene (43.57 g, 254.7 mmol), and potassium carbonate (80.01 g, 579.0 mmol) were added to DMF (500 mL) and stirred at ambient temperature overnight. Water was added and extracted with ether. The organic phase was washed with 1M NaOH, dried, filtered, and concentrated to provide the title compound (50.8 g, 99.86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH3:24][N:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[CH3:24][N:25]([CH3:30])[CH2:26][C:27]([NH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:12][CH:10]1[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]1)[CH:22]=[CH:21]2)=[O:28]
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CN(C)CC(=O)O
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) and N,N-dimethylglycine; MS: m/e=391.4 (M+H+).
Reaction SMILES: C(OC([NH:11][C:12](=[O:22])[C@@H:13]([C@H:15]([CH3:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:14])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:17]([O:16][C@@H:15]([CH3:21])[C@H:13]([C:12]([NH2:11])=[O:22])[NH2:14])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@H](OC(C)(C)C)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](OC(C)(C)C)[C@@H](N)C(N)=O

Procedure:
10% Pd/C (1.5 g) is added to a solution of the compound obtained in step (a) in MeOH (200 ml), and hydrogen is bubbled through the reaction mixture for 1.5 h, checking the disappearance of the starting compound by tlc. When the reaction is over, excess hydrogen is removed by passing a nitrogen stream through the mixture, the reaction mixture is filtered over celite and the filtrate is concentrated to dryness thus yielding O-tert-butyl-D-threonineamide (2.55 g, 99%). Both mass and NMR spectra confirm the assigned structure.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:8](=[S:10])=[S:9].O=O>C(O)(C)C>[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[C:8](=[S:10])[S:9][S:9][C:8](=[S:10])[N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: S=C=S
Agent: O=O
Solvent: CC(C)O
Product: CCCN(CCC)C(=S)SSC(=S)N(CCC)CCC
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 99.2 %

Procedure:
20.2 g (0.2 mol) of di-n-propylamine, 24.4 mg (0.1×10-3 mol) of Mn(CH3COO)2.4H2O and 100 g of isopropanol were charged to the reaction equipment described in Example 1. 16.0 g (0.21 mol) of carbon disulfide were added thereto, and the resulting solution was heated to 50° C., treated with oxygen at a pressure of 1.7 bar, and stirred vigorously. An immediate absorption of oxygen was observed and the reaction ceased after 75 minutes. 35.1 g of a white, crystalline product were obtained by concentrating and cooling the reaction solution. Upon analysis, the product was found to correspond to tetra-n-propyl thiuram disulfide (yield=99.2% of theoretical, FP=60° C.).
Reaction SMILES: [K].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.C(S)CC.[Br:14][C:15](Br)([F:17])[F:16]>CN(C)C=O>[Br:14][C:15]([F:17])([F:16])[O:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: FC(F)(Br)Br
Agent: CCCS
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc(OC(F)(F)Br)cc1
Yield: 21 %

Procedure:
According to the process, 0.1 mole of potassium salt of p-cresol is dissolved in dimethylformamide, a catalytic amount of propanethiol is added, dibromodifluoromethane is further added, and reacted at 20° to 30° C. for 4 hours to obtain p-(bromodifluoromethoxy) toluene in a 21% yield.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@@:22]([NH:44][C:45](=O)[O:46]C2C=CC([N+]([O-])=O)=CC=2)([C:30]2[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@@:22]([NH:44][C:45]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])=[O:46])([C:30]2[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][CH:21]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCC[C@H]1O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
(1R,2R)-2-aminocyclopentanol TFA salt (107 mg, 0.50 mmol) in DCM (2 mL) was added TEA (140 μL, 1.0 mmol), followed by the addition of crude (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylcarbamate (162 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 18 h, concentrated and purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-60%) over 30 min to give 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-((1R,2R)-2-hydroxycyclopentyl)urea as a pale yellow solid (110 mg, 73% yield). LCMS RT=3.90 min [M+H] 570.24 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 8.24 ppm, 1H, d, J=2.27 Hz; 7.64 ppm, 1H, dd, J=8.59, 2.27 Hz; 7.20 ppm, 1H, m; 7.12 ppm, 6H, m; 6.87 ppm, 1H, d, J=8.59 Hz; 6.62 ppm, 2H, d, J=7.07 Hz; 5.87 ppm, 1H, tt, J=53.02, 2.56 Hz; 4.91 ppm, 1H, d, J=4.04 Hz; 4.40 ppm, 1H, d, J=12.88 Hz; 3.97 ppm, 1H, q, J=6.57 Hz; 3.66 ppm, 1H, m; 3.55 ppm, 1H, d, J=12.63 Hz; 1.99 ppm, 1H, m; 1.66 ppm, 3H, m; 1.30 ppm, 2H, m.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1N1CCN2C3CCCCC=3C=C2C1=O)(=[O:3])[CH3:2].Br[C:42]1[N:47]=[C:46]([NH:48][C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH2:55][N:54]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][CH2:52]3)[C:45](=[O:66])[N:44]([CH3:67])[CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:62]([O:61][C:59]([N:54]1[CH2:53][CH2:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([NH:48][C:46]3[C:45](=[O:66])[N:44]([CH3:67])[CH:43]=[C:42]([C:7]4[CH:8]=[C:9]([F:26])[CH:10]=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[C:6]=4[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:47]=3)[CH:50]=2)[CH2:55]1)=[O:60])([CH3:65])([CH3:64])[CH3:63]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 120 °C
Yield: 57.5 %

Procedure:
A mixture of 482 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 210d and 435 mg of tert-butyl-6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydro-isoquinoline-2(1H)-carboxylate 120a, PdCl2(dppf) (1110 mg, 0.015 mmol), 2 M Na2CO3 solution (3 mL) in DME (16 mL) was heated at 120° C. under microwave irradiation for 0.5 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 129a as a yellow solid (362 mg, 51%). MS: [M+H]+ 711.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[SH:12][CH2:13][CH:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](C2SC=CC=2)=[CH:22][CH:21]=1)=[O:16].C(=O)(O)[O-].[K+]>C1(C)C=CC=CC=1>[SH:12][CH2:13][CH:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1)=[O:16]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(N[C@@H](Cc1ccc(-c2cccs2)cc1)C(=O)O)C(CS)Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C[C@H](NC(=O)C(CS)Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The operation is carried out as in Stage 1 of Example 10 using 4-methoxy benzeneboronic acid instead of thiophene-2-boronic acid, starting with 351.6 mg of methyl ester of N-[(1,1-dimethylethoxy) carbonyl]-O-[(trifluoromethyl) sulphonyl]-L-tyrosine (prepared as indicated in Stage 1 of Example 10), 10 ml of toluene, 250 mg of 4-methoxybenzene boronic acid, 170.3 mg of potassium bicarbonate and 190.17 mg of 5-tetrakis (triphenyl phosphine) Pd(O). In this way 199 mg of expected product is obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[Cl:38][C:39]1[CH:44]=[C:43]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH:42]=[CH:41][N:40]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 2-chloropyridine-4-boronic acid to afford the desired product as a colorless foam (31%). MS (ISP): 642.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:9])[CH3:8].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:8])[CH3:9])(=[O:24])(=[O:23])[NH2:22]
Reactant: CCNC(=O)NC(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CCNC(=O)NC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from 1-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea (Example 230b) and sulfamoyl chloride in 100% yield. MS 356 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.[CH2:18]([Li])CCC.CCCCCC.CI>O1CCCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:18])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution 5-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 10.0 g, 32.2 mmol) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (2.5 M, 19.3 mL, 48.2 mmol) dropwise. After stirring for 20 min at −78° C., methyl iodide (13.72 g, 96.6 mmol) was added. The resulting mixture was stirred for 2 h, quenched with a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2×200 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to give 1-(tert-butyl-dimethyl-silanyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine (7.92 g, 100%) which was used in the next step without purification: LC/MS m/e calcd for C14H22N2Si [M+H]+ 247.43, observed 247.0.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[Br:13]>S(=O)(=O)(O)O>[Br:13][C:7]1[C:6]([F:5])=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[CH:9][C:8]=1[F:12]
Reactant: Fc1cccc(F)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 10 ml concentrated HNO3 and 10 ml concentrated H2SO4 was added dropwise with cooling to a stirred solution of 30 g 2,6-difluorobromobenzene in 50 ml of concentrated sulfuric acid. The rate of addition was controlled such that the temperature of the mixture did not rise above 55° C. After the addition was complete the reaction mixture was allowed to stir at room temperature for 2 hours. It was then poured onto ice and the resulting solid was collected by filtration, washed with water and dried, yielding a pale yellow solid, m.p. 50°-51.5° C., 84% yield (31.2 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[N:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)=[N:30][CH:29]=1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)c1ccc(S)nc1
Product: COC(=O)c1ccc(Sc2cnc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)s2)nc1
Yield: 20.1 %

Procedure:
6-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-nicotinic acid methyl ester (100 mg, 20%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 6-mercapto-nicotinic acid methyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]([F:58])([F:57])[CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:54]3[CH2:55][CH2:56][CH:51]([C:50]([F:58])([F:57])[F:49])[CH2:52][CH2:53]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(C(F)(F)F)CC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-trifluoromethylpiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)[CH:18]=[CH:19][CH:20]=1.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:43]([CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:44]=[N-:45]
Reactant: OC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)-(phenyl)methanol (1.63 g, 4.24 mmol) in toluene (10 mL) under an atmosphere of nitrogen, diphenylphosphoryl azide (1.10 mL, 5.10 mmol) and DBU (0.77 mL, 5.11 mmol) was added. The reaction mixture was stirred at 45° C. for 3 hours and then at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford impure title compound (1.11 g, 64%). This material was used directly in the next step.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CN(C)C=O>O>[F:21][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:26]3[C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]4[C:22]3=[O:32])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1O[C@@H](CCl)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
The mixture of (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone (60 g), potassium phthalimide (40 g) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to 2 L water and filtered the solid to give 50 gm (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][S:34]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:36])=[O:35]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CC(C)CCS(=O)(=O)Cl
Product: CC(C)CCS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(3-Methyl-butane-1-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and 3-methyl-butane-1-sulfonyl chloride, following the general synthetic procedures described in the above Examples.