Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=O.C[Si](C)(C)N[Si](C)(C)C.[Na].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=C1OCc2ccccc21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 27.8 %

Procedure:
To a solution containing 5-chlorooxindole (0.30 g, 1.79 mmol) and phthalide (0.312 g, 2.33 mmol) in 6.0 mL of dimethylformamide (DMF) was added 3.76 mL of sodium hexamethyldisilazane (1.0 M in tetrahydrofuran (THF)) over 1 min. The solution was stirred at room temperature for 25 min and then 85 mg (0.634 mmol) phthalide was added. After an additional 20 min at room temperature the mixture was poured into 70 mL of 4% aqueous HCl solution to give a yellow solid. The aqueous mixture was extracted with EtOAc and the organic phase washed with saturated NaHCO3, brine and then dried with Na2SO4. After removal of the solvent in vacuo, the solid residue was recrystallized from MeOH/EtOAc to afford the title (141 mg, 28%) compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2](=[O:27])[CH2:3][O:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@@H:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[O:4][CH2:3][C:2]([NH2:1])=[O:27])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCC(N)=O)c2cccc(Cl)c2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CO[C@@H](c1cccc(Cl)c1F)C1CCCNC1
Yield: 96 %

Procedure:
A solution of (R)-tert-butyl 3-((2-amino-2-oxoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (100 mg, 0.25 mmol) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 30 min. The solvent was neutralized by adding saturated NaHCO3, extracted three times with CH2Cl2 and dried over Na2SO4. Evaporation of the solvent gave (R)-2-((3-chloro-2-fluorophenyl)(piperidin-3-yl)methoxy)acetamide (72 mg, 0.24 mmol, 98%). MS (E/Z): 301 (M+H+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=[O:7].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:24]=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][N:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[CH:4]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Under inert atmosphere, a mixture of 2-Trifluoromethyl-isonicotinic acid (1.0 equiv.), BOP (1.2 equiv.), DIPEA (1.5 equiv.) in DCM (C=0.1 molL−1) and MeOH (C=0.1 molL−1) was stirred at RT for 16 h. The reaction mixture was evaporated to dryness. The resulting residue was hydrolysed with HCl 1N and extracted twice with Et2O. The organic layers were combined, washed with a saturated solution of NaHCO3, brine, dried over MgSO4, concentrated to afford the product as transparent oil in a 66% yield.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:58]>CO>[ClH:58].[ClH:58].[OH:8][C@@H:7]1[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4][C@@H:3]1[CH2:2][NH:1][CH2:35][C:33]1[CH:32]=[CH:31][C:28]2[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=2[N:34]=1
Reactant: COc1ccc2ccc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2c1
Product: Cl
Reaction time: 18 h
Yield: 40 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-(methyloxy)-2(1H)-quinolinone (146 mg, 0.460 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis, see WO2004058144, Example 7(d)) (98 mg, 0.506 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (306 mg, 1.38 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale yellow oil (91 mg, 40%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:35][CH3:36])[CH2:5][CH2:6][N:7]([S:28]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:30])=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:3].ClCl.Cl.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:35]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]([S:28]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:30])=[O:29])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([Cl:1])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:36]
Reactant: Cl
Reactant: CCCCS(=O)(=O)N(CCN(CC)CC)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCS(=O)(=O)N(CCN(CC)CC)c1ccc(C(Cl)=C(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
N-(2-Diethylaminoethyl)-4'-(β-phenylstyryl)butanesulfonanilide hydrochloride (10.5 g., 0.02 mole, refer to Procedure 51) is dissolved in a mixture of 300 ml. of carbon tetrachloride and 20 ml. of chloroform. The mixture is stirred and 39 ml. of a carbon tetrachloride solution containing 1.4 g. (0.02 mole) of chlorine is added thereto during 30 min. The mixture is kept at room temperature for an additional 30 min. and then refluxed for 1 hr. Vigorous evolution of hydrogen chloride gas is apparent during this period. The reaction mixture is allowed to cool and then neutralized with 100 ml. of aqueous 5% sodium hydroxide. The organic layer is separated, dried over magensium sulfate, and the solvent evaporated yielding 11.0 g. of the desired product. The material is purified by chromatography on an alumina column having dimensions 1 inch by 15 inches and eluting sequentially with 1:1 benzene-octane; benzene; benzene-chloroform, and finally with chloroform and collecting the eluate in 20 fractions. Fractions 15-19 are combined and the desired product recovered as the citrate salt, m.p. 65°-70°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1C=C(N2CCCCC2)C=CC=1N)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=O>C(Cl)Cl>[CH3:1][O:3][C:4]([C:5]1[C:24]([NH:19][C:30](=[O:32])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([CH2:26][Cl:25])[CH:28]=2)=[CH:23][C:22]2[C:21](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:20]=1)=[O:18]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccccc2cc1NC(=O)c1cccc(CCl)c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
3-Amino-naphthalene-2-carboxylic acid methyl ester (compound A) (530 mg) produced by the above process was dissolved in anhydrous methylene chloride (10 ml). Pyridine (0.5 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (0.6 ml) was added dropwise to the solution at room temperature, and the mixture was then stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was concentrated under the reduced pressure to precipitate crystals. The crystals were collected by Kiriyama Rohto and were washed with a hexane-ether solvent to give 3-(3-chloromethylbenzoylamino)-naphthalene-2-carboxylic acid methyl ester (870 mg, yield 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[C:20][CH3:21].C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=[O:56])C>O.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.[Cu]I>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:21][C:20]([CH2:19][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:56])=[CH:3][CH:4]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(Br)cc1
Reactant: CN(C)C=O
Reactant: CC#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCNCC
Product: Cc1sc2ncnc(N)c2c1-c1ccc(CC(=O)Cc2ccccc2)cc1
Temperature: 120 °C

Procedure:
A mixture of Example 66A (100 mg, 0.31 mmol), 2-propynylbenzene (0.042 mL, 0.34 mmol), Pd(PPh3)2Cl2 (11 mg, 0.016 mmol), CuI (3 mg, 0.016 mmol), diethylamine (0.48 mL, 4.68 mmol), and triphenylphosphine (16 mg, 0.062 mmol) in DMF (0.5 mL) in capped 5 mL vial was stirred while heating to 120° C. for 25 minutes in a Smith Synthesizer microwave at 300 W. The mixture cooled using 40 psi pressurized air, diluted with water, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by silica gel chromatography with ethyl acetate to provide 38 mg of the desired product. MS (ESI(+)) m/e 374 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H); 3.91 (s, 2H); 3.97 (s, 2H); 7.16-7.36 (m, 9H); 8.27 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].F[C:31](F)(F)[CH:32]([CH3:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[CH:32]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[C:17]([F:29])([F:28])[F:16])(=[O:26])=[O:25])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:36][CH:35]=1)([CH3:41])[CH3:31]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 551.14 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethyl-benzenesulfonyl chloride, 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCOCC.[Mg+2].[Br-].[Br-].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[C:34]=2[CH:39]=[O:40])=[CH:29][CH:28]=1>C1COCC1>[CH2:1]([C:8]1[O:9][C:10]([CH:39]([C:34]2[C:35]([CH3:38])=[N:36][O:37][C:33]=2[C:30]2[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=2)[OH:40])=[N:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nnco2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
2-Benzyl-[1,3,4]oxadiazole (0.500 g, 3.12 mmol) was dissolved in THF and cooled to −70° C. then n-butyllithium (1.5M in THF, 2.1 mL, 3.12 mmol) was added and the reaction stirred for 1.5 hours. Magnesium bromide ethyl etherate (0.631 g, 3.43 mmol) was added and the reaction was allowed to warm to −45° C. After 45 minutes 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.415 g, 1.56 mmol) in THF (2 mL) was added and the reaction was allowed to stir overnight. The reaction was quenched with aqueous ammonium chloride then submitted to standard workup and purification via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][OH:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[C:19]([C:20]([NH:22][NH:23][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][OH:14])=[O:21])=[CH:18][N:17]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (500 mg, 2.4 mmol) and 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (2.6 mmol, 1.1 equiv.) in DMF (10 mL), DIPEA (12 mmol, 5 equiv.) and HATU (2.6 mmol, 1.1 equiv.) were added and stirred overnight at room temperature. The reaction mass was concentrated under reduced pressure to remove excess of solvent present. Diluted the residue with EtOAc and washed water followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get tert-butyl (1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate (53).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)#N.[OH2:16].[OH-:17].[Na+]>C(O)C>[CH:13]([C:12]1[C:4]([CH2:3][C:1]([OH:17])=[O:16])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)([CH3:15])[CH3:14]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)c1cc2c(cc1CC#N)OCO2
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1cc2c(cc1CC(=O)O)OCO2
Reaction time: 20 h

Procedure:
6.22 g of 5-cyanomethyl-6-isopropyl-1,3-benzodioxole (crude oil) was dissolved in 120 ml of ethanol, followed by the addition of 40 ml of water and 12.24 g of sodium hydroxide. The obtained mixture was stirred for 20 hours, while keeping the temperature of an oil bath at 100° C. The reaction mixture was concentrated, followed by the addition of water. The obtained mixture was washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain 6.31 g of the title compound as a crude crystal.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:43][CH2:42][C:15]([CH3:44])([O:16][CH2:17][CH:18]=[CH:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[C:28]([CH2:29][O:30][CH2:31]3)=[CH:27][CH:26]=[C:25]([Cl:40])[CH:24]=2)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:13][CH2:14][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[C:28]([CH2:29][O:30][CH2:31]3)=[CH:27][CH:26]=[C:25]([Cl:40])[CH:24]=2)[CH2:42][CH2:43]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(Cl)ccc1COC3
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(Cl)ccc1COC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of (2S)-2-(tert-butoxy)-2-[(20S)-16-chloro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (0.020 g, 0.032 mmol) in ethanol (1 mL) was added Hoveyda-Grubbs catalyst 2nd generation (4.00 mg, 6.38 μmol). Sodium borohydride (6.03 mg, 0.159 mmol) was added and the mixture was stirred at rt. After 30 min, the reaction was quenched by careful addition of water. The product was extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-16-chloro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17-heptaen-3-yl]acetic acid (6.1 mg, 9.70 μmol, 30.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.32 (d, J=8.1 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.48 (s, 1H), 5.63 (br. S., 1H), 4.84 (d, J=12.5 Hz, 1H), 4.69-4.48 (m, 4H), 4.32 (t, J=11.9 Hz, 1H), 3.65 (br. S., 1H), 3.35-3.22 (m, 4H), 2.74 (s, 3H), 2.02-1.40 (m, 10H), 1.26-0.95 (m, 15H). LCMS (M+H) calcd for C33H46ClN4O6: 629.31. found: 629.4.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]12[NH:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9]2.C(N(CC)CC)C.Br[CH2:30][C:31]1[S:39][C:38]2[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[N:36][C:35]([Cl:46])=[N:34][C:33]=2[CH:32]=1>C1COCC1>[Cl:46][C:35]1[N:36]=[C:37]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:38]2[S:39][C:31]([CH2:30][N:15]3[CH:8]4[CH2:14][CH2:13][CH:12]3[CH2:11][N:10]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:9]4)=[CH:32][C:33]=2[N:34]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: O=C(N1CC2CCC(C1)N2)C(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(N1CC2CCC(C1)N2Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 71 %

Procedure:
To a solution of 1-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2,2,2-trifluoro-ethanone trifluoroacetic acid salt (106 mg, 0.33 mmol) in THF (5 mL) were added triethylamine (161 μL, 1.16 mmol) and 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (100 mg, 0.29 mmol). The reaction mixture was stirred at RT for 17 h, then concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (98 mg, 71%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:28][C:29]1[CH:46]=[CH:45][C:32]2[N:33]([CH2:43][CH3:44])[C:34](=[O:42])[C:35]([CH3:41])([CH3:40])[C:36](=[O:39])[N:37]([CH3:38])[C:31]=2[CH:30]=1)[CH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][CH:17]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:43]([N:33]1[C:34](=[O:42])[C:35]([CH3:40])([CH3:41])[C:36](=[O:39])[N:37]([CH3:38])[C:31]2[CH:30]=[C:29]([CH2:28][NH:14][CH2:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]4[CH3:26])=[CH:18][CH:17]=3)[CH:46]=[CH:45][C:32]1=2)[CH3:44]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc4c(c3)N(C)C(=O)CC4)C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(C)C(=O)CC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (43.2 mg) was added to a dichloromethane solution (5 ml) of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)carbamic acid tert-butyl ester (208 mg), and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane, and condensed under reduced pressure to give the title compound (148 mg) as a white amorphous.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][C:11](=[O:29])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23](CBr)=[C:22]([CH3:28])[CH:21]=2)=[CH:14][CH:13]=1)[CH3:9].[CH2:30](OC(=O)C1C=CC(CC(C)C2C=CC(CBr)=CC=2)=CC=1)C>CN(C=O)C>[CH2:8]([O:10][C:11](=[O:29])[C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[C:22]([CH3:28])[C:21]=2[CH3:30])=[CH:16][CH:17]=1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(CC(C)c2ccc(CBr)cc2)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CBr)c(C)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2ccc(-n3ccnc3)c(C)c2C)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF was treated with NaH (11.0 mg, 0.44 mmol) and heated to 90° C. After 1 h a solution of ethyl4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate (Intermediate 137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added and stirring at 90° C. continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 90.0 mg (71%) was isolated by column chromatography (20-100% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@H:7]1[C@H:11]([C:12]([O:14]C)=[O:13])[O:10][C:9]([CH:29]([Br:31])[CH3:30])([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=3[Br:26])[CH:17]=2)[O:8]1)=[O:6]>O.CO>[Br:31][C@H:29]([C:9]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=3[Br:26])[CH:17]=2)[O:10][C@@H:11]([C:12]([OH:14])=[O:13])[C@H:7]([C:5]([OH:6])=[O:4])[O:8]1)[CH3:30]
Reactant: COC(=O)[C@@H]1OC(c2ccc3c(Br)c(OC)ccc3c2)(C(C)Br)O[C@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C3([C@H](C)Br)O[C@@H](C(=O)O)[C@H](C(=O)O)O3)ccc2c1Br
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (5.32 g, 0.133 mol) in water (70 ml) was added dropwise in 1 hour, under stirring, to a solution of the diastereoisomer 3 (35.4 g, 0.665 mol) in methanol (250 ml) at 20° C. The reaction mixture was kept at 20° C. for 2 hours; then methanol was removed under reduced pressure mantaining the initial volume of the solution by addition of water. The aqueous solution, so obtained, was extracted with dichloromethane, acidified with conc HCl to pH 1, and extracted with diethylether (3×100 ml). The combined organic extracts were washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo. Crystallization of the residue from dichloromethane gave the pure 2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer 7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])=[C:11]([Cl:22])[C:10]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6](=[O:28])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])=[C:11]([Cl:22])[C:10]([NH:23][CH2:24][C:25](=[O:27])[CH3:26])=[N:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(=O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of 4-(4-bromo-2-chlorophenylamino)-5-chloro-6-(2-hydroxypropylamino)-nicotinic acid tert-butyl ester (0.28 g, 0.57 mmol) in acetonitrile (1.1 mL) was added 4A molecular sieves and N-methylmorpholine (0.10 g, 0.85 mmol). The mixture was cooled to 0° C. and tetrapropylammonium perruthenate (0.030 g, 0.085 mmol) was added. After stirring for one hour, the reaction was filtered through a plug of silica gel, washing with EtOAc. The filtrate was concentrated. Purification by flash column chromatography (20:1 hexanes/ethyl acetate) provided the desired product as a white solid (86 mg, 31%). MS APCI (+) m/z 490, 492 (M+, Cl, Br pattern) detected.