Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:24]OCC)[CH:21]=4)[NH:16][N:15]=3)[CH:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][NH:29][C:30](=O)[CH2:31][N:32]([CH3:34])[CH3:33].C[O-].[Na+]>CO>[CH3:33][N:32]([CH2:31][C:30]1[N:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)[NH:28][N:29]=1)[CH3:34]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CCC4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CCC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclobutyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (460 mg, 1.06 mmol), N-amino-2-(dimethylamino) acetamide (372 mg, 3.17 mmol) and sodium methoxide (608 μL of a 25% w/w in methanol) in anhydrous methanol (7.0 mL) with a reaction time of 44 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a pale yellow solid. The residue was dissolved in a minimum amount of anhydrous methanol and excess 1.0 N HCl in anhydrous ethyl ether was added dropwise to precipitate the desired product as the bis-hydrochloride salt. The product was collected and dried under vacuum to afford the title compound (27 mg, 5% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 10.6 (br s, 1H), 8.89 (d, 1H), 8.84 (s, 1H), 8.4 (s, 1H), 8.17 (d, 1H), 8.12 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.63 (t, 1H), 4.5–4.4 (m, 1H), 4.44 (s, 2H), 2.83 (s, 6H), 2.23–2.0 (m, 4H), 1.72–1.62 (m, 2H); ES-MS (m/z) 416 [M+H]+ (HCl salt not detected).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 93.2 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (994 mg, 2.73 mmol) and phenyl boronic acid (576 mg, 3.00 mmol) according to the general procedure B. Obtained as a bright yellow solid (800 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl>[OH:4][CH2:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CC(=O)OCC[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CCO)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
To a solution of 34 mg of t-butyl (3S)-3-(2-acetyloxyethyl)-pyrrolidine-1-carboxylate in 1 ml of methanol, 54 mg of potassium carbonate was added, and stirred for 2.5 hours at room temperature. The reaction liquid was diluted with chloroform, washed successively with water and saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 29 mg of the title compound was obtained.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].C(N(CC)CC)C>ClCCl>[C:21]([CH2:23][C:24]([NH:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:10])=[O:6])[CH3:4])=[O:25])#[N:22]
Reactant: N#CCC(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC#N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
1.7 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 50 ml of dichloromethane at 0° C. 0.42 g (0.005 mol) of cyanoacetic acid, 0.7 ml (0.005 mol) of triethylamine and 1.1 g of N,N-dicyclohexylcarbodiimide were added and the mixture was stirred at 0° C. overnight. The solvent was removed by evaporation, the residue suspended in 50 ml of ethyl acetate, the suspension filtered and the filtrate washed with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated to give a white solid. Recrystallisation of this solid from ethyl acetate yielded 0.6 g (37%) of N-cyanoacetyl-L-alanyl-L-proline anilide of melting point 183°-184° C.; [α]D20 =-204.6° (c=0.78% in methanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]1([S:39](Cl)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.O>C(Cl)Cl>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([S:39]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)(=[O:41])=[O:40])[CH2:13][CH2:12]3)=[O:28])=[CH:22][CH:21]=2)[CH:27]=[N:26][N:25]=[N:24]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(-n3cnnn3)cc2)CC1
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccc(-n2cnnn2)cc1)N1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
In a two neck round bottom flask, 2-(4-(1H-tetrazol-1-yl)phenoxy)-1-(piperazine-1-yl)ethanone hydrochloride (compound 3, 0.882 mmoles, 0.286 g, 1 eq) and 1-naphthalene sulfonylchloride (0.882 mmoles, 0.2 g, 1 eq) were charged in DCM (20 mL). TEA (2.646 moles, 0.267 g, 3 eq) was added drop wise to the reaction mixture over a period of 10 min at 0° C. The resulting mixture was stirred for 3 h at room temperature and monitored by TLC. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 3:7, Ethyl acetate/Hexane) to obtain the title compound (0.300 g, 71.09%) as off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:35][CH2:36][O:37][CH3:38].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:35][CH2:36][O:37][CH3:38])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:24]=2)=[N:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc(N(CCOC)C(=O)OCc3ccccc3)cn2)cc1
Reaction time: 0.58 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-[4-(5-benzyloxycarbonylaminopyridin-2-yloxy)phenyl]propionate (1.7 g, 4.0 mmol) in DMF (50 mL) was added 60% sodium hydride (0.19 g, 4.9 mmol) under ice cooling, and the resulting solution was stirred for 35 minutes at the same temperature. 2-Bromoethylmethyl ether (0.4 mL, 4.2 mmol) was added dropwise to the solution. The reaction solution was stirred for 2 hours under ice cooling, and then stirred for 2 days at room temperature. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6](O)=[O:7].C(O)(=O)C.[CH:17](N)=[NH:18]>CCO>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)[N:12]=[CH:17][N:18]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ncnc2cc(F)c(F)cc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A mixture of 4,5-difluoroanthranilic acid (20.43 g, 118 mmol) and formamidine acetate (13.55 g, 130 mmol) in reagent EtOH was stirred at 120° C. (oil bath) for 3 hr. The reaction was briefly a homogeneous brown solution, and then became an opaque mixture. The reaction was allowed to cool to rt, and the resulting solid was filtered, washed with denatured EtOH (1×10 mL), and allowed to air dry. Powdering with a mortar and pestle provided 4-hydroxy-6,7-difluoroquinazoline as a beige powder (16.9 g, 79%). 16.6 g of this material (91.1 mmol) was taken up in SOCl2 (66 mL), DCE (66 mL), and DMF (7.05 mL, 91 mmol), and was stirred at 110° C. (oil bath) for 1 hr. The resulting homogeneous amber solution was then concentrated under rotary evaporation, and taken up in toluene (2×100 mL) with repeated rotary evaporation to provide the crude title compound as a beige solid. A portion of this material (8.4 g of 17.7 g total) was taken up in DCM (80 mL) and gently shaken with 2M trisodium citrate (1×40 mL) until a homogeneous clear organic layer resulted. This organic layer was immediately applied (without drying) directly onto a silica flash column (79 mm×6″) pre-equilibrated with 1:1 hexanes/EtOAc. Trivial elution with 1:1 hexanes/EtOAc, followed by repeated rotary evaporation from toluene (2×50 mL) of the combined fractions afforded the title compound as a light yellow solid (6.79 g, 78%). 1H-NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.05 (dd, 1H), 7.86 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl-].[Br:16][C:17]1[C:18]([OH:45])=[C:19]([CH2:25][P+:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl-:1].[Br:16][C:17]1[C:18]([O:45][C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[C:19]([CH2:25][P+:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1cc(Br)c(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)N1CCC(C(=O)Oc2c(Br)cc(OC)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 66 %

Procedure:
With the exclusion of air, 43.9 g of 4-chlorocarbonyl-1-ethoxycarbonyl-piperidine are dissolved in 250 ml of anhydrous acetonitrile (degassed) and 53.4 g of [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride are added to the solution. In the course of 30 minutes, at 25° to 30°, 20 g of pyridine are added dropwise to the resulting suspension. The mixture is heated for 5 hours under reflux and is then hydrolysed with 100 ml of sodium carbonate solution (15%); the organic phase is separated off, washed in succession with 100 ml of 1N hydrochloric acid and 100 ml of water and concentrated by evaporation in vacuo and the oily residue that remains is dissolved in 50 ml of dichloromethane. In the course of 30 minutes, at 20°, with vigorous stirring, 200 ml of ethyl acetate are added dropwise to that solution and the product crystallises out. The resulting crystal suspension is concentrated to 150 ml under a weak vacuum using a rotary evaporator and then stirred for 2 hours at 0°. Filtering with suction and drying yield [(3-bromo-2-[(1-ethoxycarbonylpiperid-4-yl)carbonyloxy]-5-methoxy-phenyl)methyl ]-triphenyl-phosphonium chloride [m.p.: 196°; IR (KBr): 3415, 3060, 2855, 2780, 1600, 1565, 1385, 1270, 1190, 1165 cm-1 ; 1 H-NMR (360 MHz, CDCl3); 1.28 (t, 3H, CO2CH2CH3), 1.45 (m, 2H), 1.75 (m, 2H), 2.58 (m, 1H), 2.87 (m, 2H), 2.47 (s, 3H, OCH3), 4.00 (m, 2H), 4.13 (q, 2H, CO2CH2CH3), 5.37 (br, d, 2H, CH2P+), (dd, 1H), 7.07 (dd, 1H), 7.54 to 7.87 (m, 15H) ppm]; yield 66% of the theoretical yield.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[C:7]([N:6]1[C:2]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(Cl)cc1
Yield: 38 %

Procedure:
A mixed solution of 2-[2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl]-N-[(tetrahydro-2H-pyran-4-yl)methyl]acetamide (44.1 mg, 100 μmol), 4-chlorophenylboronic acid (15.6 mg, 100 μmol), potassium carbonate (27.6 mg, 200 μmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.08 mg, 10.00 μmol) in 1,2-dimethoxyethane (0.5 mL) and water (0.5 mL) was stirred at 150° C. for 30 min under ultrasonic irradiation. To the reaction solution was added water (1 mL), the mixture was extracted with ethyl acetate (2 mL), and the organic layer was concentrated. The residue was purified by preparative HPLC to give the title compound (17.9 mg, 0.038 mmol, 38%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([S:10][C:11]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=2[CH2:13]Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CS(C)=O>[C:4]1([S:10][C:11]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=2[CH2:13][C:1]#[N:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(Sc2ccccc2)c(CCl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Temperature: 40 °C
Reaction time: 9 h

Procedure:
11.2 g of sodium cyanide in 135 ml of dimethyl sulphoxide are warmed to 40° c and treated dropwise over a period of 10 minutes with a solution of 87 g of 2-(phenylthio)-5-trifluoromethyl-benzyl chloride in 72 ml of dimethyl sulphoxide. The mixture is stirred at 40° C for 9 hours, cooled to room temperature, treated with 200 ml of water and extracted with 200 ml of ether. The aqueous phase is then extracted twice with 100 ml of ether each time. The combined organic phases are now washed twice with 200 ml of water each time, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 2-(phenylthio)-5-trifluoromethyl-phenylacetonitrile as a dark-red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:34]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>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[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)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:55])[CH2:34]3)=[O:25])=[N:14]2)=[CH:19][CH:18]=1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
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: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.54 g, 1.2 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.565 g, 55%). LCMS calc. for C40H52BrN6O6Si [M+H]+: m/z=919.3. found: 819.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=O)[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].B.C1COCC1.CO>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.545 mmol) in THF (3 mL) was treated with BH3-THF complex (15.45 mL, 15.45 mmol, 1.0 M in THF), and the resulting orange solution was refluxed overnight. The reaction was cooled in an ice-bath. MeOH (15 mL) was added, and the reaction was then concentrated. A second portion of MeOH (20 mL) was added, and the solution was refluxed for 2 hours. At this time, the reaction was concentrated, and the residue was subjected to flash chromatography on silica gel (10% EtOAc:90% hexane followed by 30% EtOAc:70% hexane). An orange solid was obtained after drying under reduced pressure. (240 mg, 86%). 1H-NMR (DMSO-d6) δ 7.68 (dd, J=2.4, 8.9 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J=2.4 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.15 (t, J=4.2 Hz, 2H), 3.45-3.40 (m, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:48][CH:49]=[CH:50][N:51]=3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:48]1[CH:49]=[CH:50][N:51]=[C:47]1[C:44]1[CH:45]=[CH:46][C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[CH:9]=3)[NH:4][CH:3]=2)=[CH:42][CH:43]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(-c5ncc[nH]5)cc4)c3c2)cc(OC)c1OC
Yield: 22.1 %

Procedure:
3-Iodo-1-(toluene-4-sulfonyl)-5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate CJ, 30 mg, 0.053 mmol), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole (Intermediate CG, 18 mg, 0.064 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.003 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (1 ml) and stirred at 60° C. for 2 d. Additional Intermediate CG (18 mg, 0.064 mmol) was added and stirring was continued for another day. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-5% MeOH:DCM to yield 5 mg (22%) of the title compound. MS ESI (m/z): 427.2 (M+1)+, calc. 426.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([OH:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:14][C:15]#[CH:16].C1COCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:16][C:15]#[CH:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1cccc(S(=O)O)c1
Solvent: O
Solvent: C1CCOC1
Product: C#CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 53.3 %

Procedure:
93.5 g (0.5 mol) of 3-nitrobenzenesulfinic acid were dissolved in 500 ml of water at pH 6.5 and the solution was added to a solution of 65.5 g of 3-bromo-prop-1-yne and 70 ml of THF. The reaction mixture was heated at 40°-50° C. until the reaction had ended (check by TLC). The reaction product was extracted with about 1.5 l of ethyl acetate, and the organic phase was neutralized and dried over sodium sulfate. The solvent was evaporated off to leave 60 g of 3-nitro-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 250°-255° C.). ##STR29##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:23][C:5]1[CH:4]=[CH:3][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:22][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@@H](Cc1ccc(Br)cc1)C(=O)O)c1cc(Br)ccc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1Cl
Yield: 91.7 %

Procedure:
(2S)-(5-Bromo-2-chloro-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid (100 mg, 0.21 mmol) was reacted with 4-trifluoromethyl-phenyl-boronic acid (243 mg, 1.2 mmol) by following general procedure D yielding the title compound (114 mg, 75%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][OH:16])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COCCOCCl
Reactant: COC(=O)c1cccc2c1ccn2CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCn1ccc2c(C(=O)OC)cccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of -(2-Hydroxy-ethyl)-1H-indole-4-carboxylic acid methyl ester in DCM (3 ml) is added DIPEA (0.129 ml, 0.739 mmol) and 1-Chloromethoxy-2-methoxy-ethane (0.084 ml, 0.739 mmol). The solution is stirred at room temperature for 72 hours. The reaction is diluted with DCM (50 ml) and washed with 0.5 M HCl (20 ml), 1 M NaOH (20 ml) and 0.5 M HCl (20 ml). The organic layer is dried over MgSO4 and the solvent is removed in vacuo. Purification by chromatography (SiO2, DCM/MeOH) affords 1-[2-(2-Methoxy-ethoxymethoxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 308