Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([O:16][CH3:17])[C:4]=1B(O)O.[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[CH3:22].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][N:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[CH:6][C:5]=2[O:16][CH3:17])=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[Cl:34])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CN2CCSCC2)cc(OC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CN3CCSCC3)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture of 2,6-dimethoxy-4-(thiomorpholinomethyl)benzeneboronic acid (1.1 g), N-(2,6-dichlorobenzoyl)-4bromo-L-phenylalanine ethyl ester (0.71 g), Pd(PPh3)4 (1.0 g) and K2CO3 (1.00 g) in DME/H2O (10 mL/0.5 mL) was heated at 80° C. for 6 h under N2. The mixture was worked up and purified according to the procedure described in Example 8-3) to yield 0.15 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(thiomorpholinomethyl)phenyl]-L-phenylalanine ethyl ester. mp. 86-89° C. ESMS: m/z 616 (MH+). HCl salt: mp. 204-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 59.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.46 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16].C(N(CC)CC)C>C(O)CCC>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1cccc(CNc2ncnc3nc[nH]c23)c1
Temperature: 90 °C
Yield: 95 %

Procedure:
3 mmol of 6-chloropurine were dissolved in 15 ml of butanol. Subsequently, 4 mmol of 3-chlorobenzylamine and 5 mmol triethylamine were added and the mixture was heated at 90° C. for 4 hours. After cooling, the precipitated product was filtered off, washed with cold water and n-butanol and crystallised from ethanol or dimethylformamide. M.p.=252° C., TLC (CHCl3:MeOH:conc. NH4OH (8:2:0.2, v/v/v)): single spot; HPLC: purity>98%. Yield 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@@H:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@@H:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 86 %

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-[(2R)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: 86%; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460/462 (chlorine isotope) and (M−H)−=458/460 (chlorine isotope).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@@H:12]([NH:14][CH2:15][C@@H:16]([C:25]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29](=[O:43])[NH:30]3)[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:13])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:25]([C@@H:16]([O:17][Si:18]([C:21]([CH3:22])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH2:15][NH:14][C@@H:12]([CH3:13])[CH2:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:44])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:26]2[C:31]=1[NH:30][C:29](=[O:43])[CH:28]=[CH:27]2)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)Cc1cccc(C[C@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of (3-{(S)-2-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethylamino]propyl}phenyl)acetic acid methyl ester (810 mg, 1.3 mmol) in a 3:2:1 mixture of THF/MeOH/water (4 mL) was added lithium hydroxide (158 mg, 6.59 mmol). The resulting mixture was stirred at room temperature for 3 hours and then acidified to pH 6 with concentrated aqueous hydrochloric acid. This mixture was concentrated under reduced pressure to give a yellow solid (307 mg, 39% yield), which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:21][CH2:20]2)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:20][CH2:21]2)([O:18][CH3:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
334 mg of 1-benzhydryl-3-cyclopropylazetidin-3-ol was dissolved in dimethylformamide, and 72 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. 112 μl of methyl iodide was added thereto, and the mixture was further stirred at room temperature for 2 hours. To the reaction solution was added water and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 280 mg of the objective compound.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:10](=O)[NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C(Cl)Cl.O>C1COCC1>[N:1]1([C:7]2[S:8][C:9]3[C:10](=[S:26])[NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCCc2nc(N3CCOCC3)sc21
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: S=C1NCCc2nc(N3CCOCC3)sc21
Yield: 59.4 %

Procedure:
To a stirred solution of Example 3 (0.139 g, 0.58 mmol) in THF (10 mL) was added Lawesson's reagent (2.36 g, 5.8 mmol). The suspension was stirred for 1 week. DCM (10 mL) and water (10 mL) were added. The aqueous fraction was extracted with DCM (3×15 mL). The combined organic fractions were washed with water (3×20 mL), dried (MgSO4), filtered and the solvent evaporated in vacuo. The oily residue was purified by column chromatography (SiO2, 1:1 EtOAc/hexanes). Fractions containing the title compound were concentrated and the residue washed with Et2O to give the title compound (0.088 g, 51%) as a yellow solid. δH (DMSO-d6) 9.38 (1H, s), 3.69 (4H, t, J 4.8 Hz), 3.51 (4H, t, J 4.8 Hz), 3.44-3.48 (2H, m), 2.74 (2H, t, J 7.6 Hz). LCMS (ES+), 256.0 (M+H)+, RT 2.60 minutes (Method 5).
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:3]=[O:2])=[CH:14][CH:13]=1
Reactant: COC(Cl)Cl
Reactant: Fc1cccc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(F)c2ccccc12
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
19.9 g Dichloromethyl methyl ether and 45.7 g tin chloride were dissolved in 70 ml dichloromethane. The solution was cooled to +5° C. and 20.0 g fluoronapthalene in dichloromethane (49 ml) was added over a 60 min period, while keeping the temperature at 5° C. The reaction was brought to room temperature after the addition. After 4 h the reaction was quenched by slowly pouring it into an ice/water mixture. This mixture was stirred for 15 min and left standing overnight. The dichloromethane layer was washed with water, dried (sodium sulphate), filtered through celite and concentrated in vacuo to obtain 24.0 g of 4-fluoro-naphthalene-1-carbaldehyde as an off white solid.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (318 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 100% ethyl acetate in isohexane followed by 0-20% methanol in ethyl acetate to afford the product (532 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.83 (9H, s), 2.45 (3H, s), 3.61-3.90 (4H, m), 4.47-4.60 (2H, m), 4.69 (1H, m), 6.22 (1H, m), 7.36-7.48 (3H, m), 7.51-7.57 (1H, m), 8.03 (1H, s), 8.38 (1H, s), 8.50 (1H, s), 9.27 (1H, s), 10.31 (1H, s); m/z (ES+) (M+H)+=595; HPLC tR=2.63 min.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH2:10][CH:11]([O:35][CH3:36])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])=[O:7].[S:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>>[I-:1].[CH3:36][O:35][CH:11]([CH2:10][NH:9][S:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:38]1[S:37][CH:41]=[CH:40][NH+:39]=1)(=[O:8])=[O:7])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCI)OC
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCc1[nH+]ccs1)OC
Product: [I-]
Yield: 41 %

Procedure:
A solution of 300 mg (0.464 mM) of 3-(4-iodobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane in 3 ml of thiazole is stirred at 60° C. for 6 hours. After thiazole is evaporated, the residue is washed with ether and recrystallized from ether-dichloromethane to give 140 mg (0.191 mM) of 2-methoxy-1-octadecylcarbamoyloxy-3-(4-thiazoliobutylsulfonylamino)propane iodide Ia13 in 41% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:22]Br.C(OCC)C>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH2:11][Br:22])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 2.5 h
Yield: 55 %

Procedure:
The product of step (a) (10.0 g, 35.2 mmol) was dissolved in chloroform (250 mL) in a 500 mL flask under a nitrogen atmosphere. Bromine (1.63 mL, 31.7 mmol) dissolved in chloroform (50 mL) was added using a dropping funnel over 30 min. The reaction mixture was stirred for 2.5 h and then concentrated to give a solid. The solid was dissolved in toluene (150 mL) with some gentle heat, followed by the addition of ethyl ether (150 mL) to yield the title compound as a crystalline solid (55% yield).
Reaction SMILES: Br[CH:2]([F:21])[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH2:22]C1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O.BrC(F)C(Br)=O.N>CCOCC>[F:21][CH:2]1[N:22]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]=2[NH:5][C:3]1=[O:4]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(F)Br
Agent: N
Agent: O=C(Br)C(F)Br
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F
Reaction time: 18 h

Procedure:
A solution of 3.71 g. of 2-(α-bromo-α-fluoro-acetamido)-5-chlorobenzophenone, obtainable from 2-amino-5-chlorobenzophenone and α-bromo-α-fluoroacetyl bromide, in 100 ml. of ether and 60 ml. of 13% methanolic NH3 is allowed to stand for 18 hours at 20° and is evaporated. Working up in the customary manner, using water/methylene chloride, gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)([CH3:4])[CH3:3].[H-].[Na+].I[CH3:17]>C1COCC1.CN(C=O)C>[CH3:17][O:13][C:7]1([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: C[Si](C)(C)C#CC1(O)CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1(C#C[Si](C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (0° C.) of 4-{(trimethylsilyl)ethynyl}tetrahydropyran-4-ol prepared as described in the above example (2.5 g, 12.6 mmol) in a THF-DMF mixture (55 mL, 10:1), sodium hydride (60% suspension in oil, 0.504 g, 12.6 mmol) was added portionwise. After addition, the mixture was stirred 15 minutes before iodomethane (0.788 mL, 12.6 mmol) was added. The temperature was slowly raised to room temperature and the reaction was stirred for another 2 hours. The reaction mixture was then quenched with water and the product was extracted with ethyl acetate (2×). The combined organic layers were diluted with hexanes and washed with water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/dichloromethane, 2:98) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 3.82-3.74 (m, 2H), 3.61-3.54 (m, 2H), 3.34 (s, 3H), 1.90-1.82 (m, 2H), 1.71-1.63 (m, 2H), 0.21 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccnc(Cl)c1F

Procedure:
A solution of tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate (20.2 mmol) in 1:2 TFA/DCM (45 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography (SiO2, 100:0 to 90:10 DCM/7N NH3 in MeOH) to yield the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8]([Br:17])[N:7]=1)=O)C.O.[NH2:19][NH2:20].O>CCO>[NH2:12][C:11]1[C:6]([C:4]([NH:19][NH2:20])=[O:3])=[N:7][C:8]([Br:17])=[C:9]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 90 °C

Procedure:
To a solution of 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Int. F1) (1.00 g, 3.18 mmol) in dry EtOH (25 ml) was added hydrazine monohydrate (309 ul, 6.37 mmol) and the mixture was stirred at reflux (ca. 90° C.). After 3 hr 45 min the reaction mixture was cooled in an ice bath and added to water. The resulting yellow ppt was filtered under vacuum and dried in a vacuum oven overnight to give the title compound as a yellow solid 1H NMR (400 MHz, DMSO-d6) 610.10 (1H, s), 8.00 (2H, s), 4.65 (2H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13][NH:12]2)=[CH:2]1.N1C=CC=CC=1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](Cl)=[O:38]>ClCCl>[F:32][C:33]([F:47])([F:48])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:42]=1)[C:37]([N:12]1[C@H:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13]1)=[O:38]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)NCC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.8 %

Procedure:
To an ice-cooled solution of (5R)-5-(1H-indol-3-ylmethyl)-1-[3-(ethoxycarbonyl)propyl]piperazin-2-one (0.56 g) and pyridine (0.26 ml) in dichloromethane (10 ml) was added a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.45 g) in dichloromethane (1 ml). The solution was stirred for 40 minutes at the same temperature. After concentration, the residue was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium bicarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of dichloromethane-methanol (from 0% to 5% gradient solution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-[3-(ethoxycarbonyl)propyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.34 g) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([OH:16])[CH2:12][CH2:11]1.C[N:24](C=O)C.C1N=CN([C:33]([N:35]2[CH:39]=[N:38]C=C2)=[O:34])C=1.C(=O)(O)O.NC(N)=N>O>[C:39]([NH:35][C:33](=[O:34])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:10]2[CH2:11][CH2:12][C:13]([OH:16])([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[C:2]=1[F:1])(=[NH:38])[NH2:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cccc(N2CCC(O)(c3cccnc3)CC2)c1F
Reactant: CN(C)C=O
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: O
Product: N=C(N)NC(=O)OCc1cccc(N2CCC(O)(c3cccnc3)CC2)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-Fluoro-3-(hydroxymethyl)phenyl]-4-(pyridin-3-yl)piperidin-4-ol (187 mg), DMF (5.5 ml), and CDI (201 mg) were mixed, followed by stirring at room temperature for 2 hours. Guanidine carbonate (279 mg) was added to the reaction mixture, followed by stirring at room temperature overnight. Water was added to the reaction mixture, followed by ice-cooling and stirring for 30 minutes, and the generated solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure. The obtained solid was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 2-fluoro-3-[4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl]benzyl carbamimidoylcarbamate (160 mg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:35])[C@H:16]([N:21]2[C:27](=[O:28])[C@H:26]3[C@@H:22]2[O:23][C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]3)[C:17]([CH2:19]I)=[CH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:36]>>[C:1]1([CH:7]([O:14][C:15](=[O:35])[C@H:16]([N:21]2[C:27](=[O:28])[C@H:26]3[C@@H:22]2[O:23][C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]3)[C:17]([CH2:19][OH:36])=[CH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: C=C(CI)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Product: C=C(CO)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
To a mixture of (2R)-2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-3-iodomethyl-3-butenoic acid diphenylmethyl ester (1) in an organic solvent and inorganic base in water is added a peracid portionwise under nitrogen gas, and the mixture is stirred for the given time at the given temperature under nitrogen. The reaction mixture is washed with water, aqueous 5% sodium thiosulfate, aqueous sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated under reduced pressure. The residue is crystallized from ethanol to give (2R)-2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl]-3-hydroxymethyl-3-butenoic acid diphenylmethyl ester (2). mp. 100°-104° C.