Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[N:3]=1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>CS(C)=O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=1)(=[O:27])=[O:26])[CH:9]=[C:8]2[C:4]1[N:3]=[C:2]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(4-chloropyrimidin-2-yl)-5-(2,6-difluorophenyl)-1-tosyl-1H-indole (500 mg, 10 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (404 mg, 2.02 mmol) in DMSO (10 mL) was heated at 110° C. for 12 h. The resulting mixture was cooled to at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to the title compound (500 mg, 75%). MS (ESI, pos. ion) m/z: 660 (M+1).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([F:11])[CH:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][CH:2]([F:12])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:19]/[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[C:5]([F:11])[CH:4]=1
Reactant: O=Cc1ccc(C(F)F)cc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)F)cc1F
Temperature: 55 °C
Yield: 103.1 %

Procedure:
To a mixture of 4-(difluoromethyl)-2-fluorobenzaldehyde (162 mg, 0.930 mmol) and (R)-2-methylpropane-2-sulfinamide (124 mg, 1.023 mmol) in DCE (3 mL) was added copper sulfate (223 mg, 1.396 mmol). Reaction mixture was heated in a preheated oil bath to 55° C. for 38 hours. The mixture was allowed to cool to room temperature, filtered through a pad of celites and washed with DCE. Combined filtrates were concentrated under reduced pressure to afford (R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (266 mg) as a yellow oil, which was used without further purification. LCMS m/z 278.1 (M+H)+, Rt 0.98 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Cl[CH:29]([CH3:33])[C:30](=O)[CH3:31]>CN(C)C=O>[CH3:33][C:29]1[N:26]=[C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)[S:27][C:30]=1[CH3:31]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CC(=O)C(C)Cl
Solvent: CN(C)C=O
Product: Cc1nc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)sc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A mixture of 0.60 g (1.56 mmol) of the starting material I, 1.02 g (9.57 mmol) of 3-chloro-2-butanone and 8 ml of dimethylformamide was stirred at 90° C. for 3 h. After cooling the precipitated crystals were filtered off, dried and purified by recrystallization from dimethylformamide and water to yield 0.49 g (76%) of the title compound; Mp.: >260° C. (dec.).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([C:9]1[CH:10]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([Cl:34])=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)(=O)[CH3:7].C([BH3-])#[N:36].[Na+].Cl>CO.O>[NH2:36][CH:6]([C:9]1[CH:10]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([Cl:34])=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:7]
Reactant: CC(=O)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(N)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
Ammonium acetate (0.339 g, 4.40 mmol) was added to a solution of 2-(2-(2-(2-((3-acetylphenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide (A141) (0.120 g, 0.293 mmol) in MeOH (5 mL) and the mixture was stirred for 20 minutes under a nitrogen atmosphere. Sodium cyanoborohydride (0.013 g, 0.21 mmol) was added and the mixture was stirred for 6 hours. Additional sodium cyanoborohydride (0.013 g, 0.21 mmol) was added and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with water (10 mL), acidified with 20% aqueous HCl (10 mL) and washed with Et2O (2×30 mL). The aqueous phase was basified with solid potassium hydroxide to pH 10 and extracted with DCM (3×30 mL). The combined organic phases were washed with water, brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 12 g SiO2 Cartridge, 0-30% MeOH in DCM) to give the title compound (38) as a white foam (0.057 g, 47%). LCMS-B: rt 5.45 min; m/z 410 [M+H]+.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:11])([CH3:10])[CH:8]=[CH2:9].[BH4-].[Na+].B(F)(F)F.[OH-:24].[Na+].OO>COCCOCCOC.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:11])([CH3:10])[CH2:8][CH2:9][OH:24]
Reactant: C=CC(C)(O)c1ccccc1-c1ccccc1
Reactant: [OH-]
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: O
Product: CC(O)(CCO)c1ccccc1-c1ccccc1
Temperature: 0 °C

Procedure:
2.24 g. of 3-p-biphenylyl-1-buten-3-ol (obtainable from p-biphenylylmagnesium bromide and methyl vinyl ketone) are dissolved in 5 ml. of diglyme, 3 ml. of a 1 M solution of NaBH4 in diglyme are added and a solution of 0.56 g. of BF3 etherate in 1.2 ml. of diglyme is added dropwise under N2. 0.7 ml. of water is then added and 1.4 ml. of 3N NaOH and 1.4 ml. of 30% H2O2 are then added dropwise at 80°-100°. The mixture is cooled, treated with ice water, and standard working up gives 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117° (the boric acid ester formed as an intermediate being hydrolyzed).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.C(OC(=O)C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
{5-Chloro-2-[(R)-4-(2-1-BOC-piperazin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Step A was dissolved in dichloromethane (50 mL). 4N hydrochloric acid ethyl acetate solution (1.3 mL, 5.28 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM and ethylether to give the title compound (125 mg, Yield 55%).
Reaction SMILES: [C:1]1([C@H:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[C:1]1([C@H:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)N1CC(CO)O[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N1CC(COc2ncccc2C#N)O[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (S)-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred four hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform extract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, (S)-2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH:3]([C:12]1[N:17]=[N:16][C:15]([S:18][C:19]2[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=2[CH2:21][NH:22][C:23](=[O:37])[C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[C:26]([F:36])[CH:25]=2)=[CH:14][CH:13]=1)[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11].[CH3:43]N(C(OC)OC)C>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:11])[C:4]=1[C:3]1[C:2](=[O:42])[N:1]=[CH:43][N:17]2[C:12]=1[CH:13]=[CH:14][C:15]([S:18][C:19]1[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=1[CH2:21][NH:22][C:23](=[O:37])[C:24]1[CH:29]=[C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH:27]=[C:26]([F:36])[CH:25]=1)=[N:16]2
Reactant: NC(=O)C(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1Sc1ccc2c(-c3c(Cl)cccc3Cl)c(=O)ncn2n1)c1cc(F)cc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A solution of N-[2-({6-[2-amino-1-(2,6-dichlorophenyl)-2-oxoethyl]pyridazin-3-yl}sulfanyl)benzyl]-3-fluoro-5-(morpholin-4-yl)benzamide (91 mg, 0.145 mmol) in toluene (4 mL) under an argon atmosphere was treated with DMF-DMA (0.042 mL, 0.315 mmol). The mixture was heated at 100° C. for 1.75 h, then cooled to RT and the precipitate separated by filtration to afford the title compound (77 mg, 84%) as a yellow powder. LCMS (Method 3): Rt 9.8 min, m/z 636 [MH+]. 1H NMR (400 MHz, DMSO-d6): 9.01 (1H, t, J 5.7), 8.82 (1H, d, J 0.7), 7.70 (1H, dd, J 7.7, 1.2), 7.60 (2H, m), 7.58-7.52 (2H, m), 7.49 (1H, dd, J 8.9, 7.3), 7.42 (1H, td, J 7.3, 2), 7.23 (1H, br t, J 1.6), 7.04-6.98 (2H, m), 6.93-6.86 (2H, m), 4.66 (2H, d, J 5.6), 3.73 (4H, t, J 4.7), 3.17 (4H, t, J 4.7).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(NC(C)C)(C)C.[C:38]([O:41][CH2:42][CH3:43])(=[O:40])[CH3:39]>C1COCC1.O.C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:13]([CH3:14])[CH3:15])[C:16](=[O:18])[CH2:39][C:38]([O:41][CH2:42][CH3:43])=[O:40])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-L-valine (25.0 g) in dry THF (100 mL) was added 1,1′-carbonylbis-1H-imidazole (19.4 g) at 0° C. in small portions, and the mixture was stirred at room temperature overnight (solution 1). To a solution of diisopropylamine (30.2 g) in dry THF (330 mL) was added dropwise a 1.6 mol/L n-butyllithium-hexane solution (186.5 mL) under an argon atmosphere at −78° C. and the mixture was stirred for 30 min, and a solution of ethyl acetate (29.2 mL) in dry THF (100 mL) was added dropwise thereto. The mixture was stirred at −78° C. for 30 min and solution 1 was added dropwise and, after the completion of the dropwise addition, the mixture was further stirred at −78° C. for 1 hr. Acetic acid (25 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=50:1→1:1) to give ethyl 4-{[(benzyloxy)carbonyl]amino}-5-methyl-3-oxohexanoate as a colorless oil (yield: 24.0 g, 75%). To a solution (150 mL) of ethyl 4-{[(benzyloxy)carbonyl]amino}-5-methyl-3-oxohexanoate (12.0 g) in acetone were added potassium carbonate (10.3 g) and iodomethane (7.0 mL), and the mixture was refluxed overnight. After allowing to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=50:1→1:1) to give the title compound as a colorless oil (yield: 7.35 g, 56%).
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[C:15](=[C:18]1[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]1=[O:27])([CH3:17])[CH3:16]>C1COCC1.C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:15]([CH:18]2[C:19](=[O:27])[O:20][C:21]([CH3:25])([CH3:26])[O:22][C:23]2=[O:24])([CH3:17])[CH3:16])=[C:9]([F:14])[CH:8]=1
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Reactant: Fc1cc(Br)ccc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(C(C)(C)c2ccc(Br)cc2F)C(=O)O1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution (183 mL, 182.79 mmol) of 1M isopropylmagnesium chloride in THF was added dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene (50.0 g, 166.17 mmol) in anhydrous THF (96 mL) over 20 min at −20° C. under argon atmosphere. The reaction mixture was stirred at −20° C. for 30 min, and added dropwise to a solution of 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene (84 mL) over 20 min at −20° C., and then the used container was washed with THF (24 mL). The reaction mixture was stirred at 0° C. for 3 hr, 10% aqueous citric acid solution (200 mL) was added thereto at 0° C., and the mixture was extracted with toluene (200 mL). The organic layer was concentrated under reduced pressure to give 5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[N:8](C(OC(C)(C)C)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[OH-].[NH4+]>O>[Cl:1][C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@H]1CC(=O)N(C(=O)OC(C)(C)C)c2ncnc(Cl)c21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Temperature: 7.5 °C
Yield: 87.9 %

Procedure:
Add (R)-tert-Butyl 4-chloro-5-methyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidine-8(5H)-carboxylate (36 g, 1.0 equiv) to water (120 mL) and stir to form a suspension. Add 12N HCl (120 g, 10 equiv) drop wise at 20-30° C. and stir the mixture for 6-8 h. A solution gradually forms. Cool the solution to 5-10° C. and add concentrated ammonium hydroxide (86.4 g, 2.4 equiv) to form a suspension. Stir the suspension for 2-3 h and is filter. Wash the filter cake with cooled water (36 mL), and then slurry with cooled isopropanol (28 g). Filter the slurry and dry the filter cake in vacuo to yield (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (21 g, 87%). MS (ES) m/z=198 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:29](Br)([CH3:31])[CH3:30]>CC(CC)=O>[CH:29]([N:12]1[CH2:11][CH2:10][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)([CH3:31])[CH3:30]
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1

Procedure:
6.0 g of 4-(4-nitrophenoxy)-4-phenylpiperidine, 2.8 g of potassium carbonate and 3.0 g of isopropyl bromide are boiled under reflux in 50 ml of ethyl methyl ketone for 24 hours. The solvent is evaporated off, the residue is taken up in 100 ml of water, and the aqueous mixture is extracted with 100 ml of diethyl ether. The organic phase is dried over sodium sulfate, filtered over active charcoal and concentrated. 5.2 g of the title compound remain as a viscous, pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[CH:10][CH3:11])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>CCO>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH:10]([CH3:11])[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:12])[CH3:21])=[CH:16][CH:15]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC=CC(=O)c1ccc(F)cc1
Solvent: CCO
Product: CC(CC(=O)c1ccc(F)cc1)N[C@@H](C)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-fluorophenyl)but-2-en-1-one (13 g, 79.2 mmol) in EtOH (150 mL) was added (S)-1-(4-bromophenyl)ethanamine (32 g, 158 mmol), and the resulting mixture was stirred overnight. The solvent was removed in vacuo to give the crude 3-((S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)butan-1-one which was used for the next step without purification.
Reaction SMILES: F[B-](F)(F)F.N#[O+].[CH3:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH3:24])[C:14]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18](N)=[CH:17][C:16]=1[CH3:23].[Na+].[I-:26].[Al].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[I:26][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([C:14]2[C:9]([CH3:8])=[CH:10][N:11]=[CH:12][C:13]=2[CH3:24])=[C:16]([CH3:23])[CH:17]=1
Reactant: [I-]
Reactant: Cc1cncc(C)c1-c1c(C)cc(N)cc1C
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a stirring suspension of nitrosonium tetrafluoroborate (0.876 g, 7.50 mmol) in dry acetonitrile (10 mL) was added dropwise via syringe a solution of 10 (0.904 g, 4.00 mmol) in dry acetonitrile (15 mL) under N2 at −30° C. The reaction mixture was next stirred at −30° C. for 1 h. To the resulting yellow solution was then added dropwise in the dark a solution of anhydrous NaI (1.125 g, 7.50 mmol) in dry acetonitrile (10 mL) under N2 at −30° C. The reaction mixture was covered with aluminum foil, allowed to gradually warm to room temperature, and stirred at room temperature overnight. The resulting red solution was next decolorized using an aqueous solution of Na2S2O3 and extracted with chloroform (50 mL×3). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 8:1 chloroform: ethyl acetate, to give 0.96 g (72%) of the title compound as a yellow solid: mp 242-243° C.; 1H NMR (400 MHz, CDCl3): δ 8.397 (s, 2H), 7.520 (s, 2H), 1.908 (s, 6H), 1.838 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 148.611, 147.520, 136.983, 136.774, 130.841, 93.681, 19.488, 16.758; MS(ESI): m/z 338.2[(M+H)+, 100]; Anal. Calcd. for C15H16IN: C, 53.43; H, 4.78; N, 4.15. Found; C, 52.91; H, 4.72; N, 4.07.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=O)[CH3:16])[N:13]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]1=[O:28])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)C.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:19])[CH3:16])[N:13]([CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:12]1=[O:28])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Sc1ccccn1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)Sc1ccccn1
Reaction time: 8 h

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one (100 mg) and 2-mercaptopyridine (35 mg) in dry tetrahydrofuran (4 ml), there was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg) under ice-cooling, followed by stirring overnight. The reaction mixture was diluted with diethyl ether and water. The organic layer was separated from the aqueous layer, washed with brine, dried over sodium sulfate and distilled off to remove the solvent to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-(2-pyridylthio)carbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([N:12]([CH2:14][C:15]([NH:17][C@H:18]([C:25]([NH:27][C@H:28]([C:41]([O:43][CH3:44])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)=O>CO>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([N:12]([CH2:14][C:15]([NH:17][C@H:18]([C:25]([NH:27][C@H:28]([C:41]([O:43][CH3:44])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: O=C=O
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@@H](N)CC(C)C

Procedure:
380 mg of Z-Sta-Sar-His-Lys(Boc)-OMe in 10 ml of 95% strength MeOH are hydrogenated with CO2 -absorption until saturation after the addition of 100 mg of Pd-on-carbon (10% Pd), the solution is filtered and concentrated to dryness. After drying in a high vacuum, H-Sta-Sar-His-Lys(Boc)-OMe is obtained in the form of an amorphous powder; Rf (G)=0.18; Rf (E)=0.53.