Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C(OCC)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCCC(O)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridine (1.1 g, 6.96 mmol, purchased from Sigma-Aldrich) in diethyl ether (8 mL) at −78° C. under N2 was added butyllithium (3.1 mL×2.5 M) over 10 min. The reaction solution was stirred at −78° C. for 1.0 hr. To the mixture was added butyraldehyde (0.602 g, 8.35 mmol, purchased from Sigma-Aldrich) dropwise over 10 min. After stirring at −78° C. for 15 min, the mixture was allowed to warm to rt and stirred at rt for 1.5 hr. The reaction mixture was poured into saturated aqueous NH4Cl solution (10 mL), diluted with water (15 mL), and extracted with EtOAc (20 mL×3). The organic layers were combined, washed with water, sat. aq. NaCl solution, and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 20-80% EtOAc/Hexanes provided the title compound as a white solid. Mass Spectrum (ESI) m/z=152.1 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(OCC)C>[C:1]1([NH:7][C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Nc3ccccc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C(=O)c2c[nH]c(Nc3ccccc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of trityl protected compound (e) (50 mg, 0.084 mmol) in ethyl ether was added 2 M HCl in ether (1 mL, 1 mmol). The reaction mixture was stirred overnight and washed with saturated NaHCO3 and dried with MgSO4. Filtration and evaporation of the solvent followed by flash chromatography to yield de-protection compound 5e (18 mg, 63%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, br, 1H), 7.51-7.43 (m, 3H), 7.33 (d, 2H), 7.04 (s, 2H), 6.62 (br, 2H) 3.82 (s, 6H), 3.73 (s, 3H). MS: 352.1 (M−H)−; 354.3 (M+H)+.
Reaction SMILES: [Cl-].[Na+].[C:3]([OH:11])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH:34][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:11]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)CN
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC(=O)c1cccnc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
An ice-cold suspension of the hydrochloride salt of nicotinoyl chloride (5 grams (g), 28 millimoles (mmol)) in dichloroethane (DCE, 150 milliliters (mL)) was treated with glycine methyl ester hydrochloride (3.7 g, 29 mmol) in portions, followed by dropwise addition of triethylamine (Et3N, 15.6 mL, 0.111 moles (mol)) via syringe. The reaction mixture was allowed to come to room temperature under nitrogen over 14 hours (h), washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate (MgSO4) and purified by silica gel chromatography (ethyl acetate/hexanes gradient) to yield an orange solid (1.8 g, 33%). The aqueous washings of the crude reaction mixture were saturated with sodium chloride (NaCl), extracted with dichloromethane (CH2Cl2) and purified by silica gel chromatography (ethyl acetate/hexanes gradient) to yield a yellow solid (1.6 g, 29%; total yield 3.4 g, 62%): mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=2.2 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.15 (dt, J=8.1, 1.8 Hz, 1H), 7.42 (dd, J=8.1, 4.8 Hz, 1H), 6.84 (br s, 1H), 4.28 (d, J=5.2 Hz, 2H), 3.82 (s, 3H); ESIMS m/z 195 (M+1). Method B A mixture of nicotinic acid (10 g, 81 mmol), p-toluenesulfonyl chloride (17 g, 89 mmol), benzyltriethylammonium chloride (1.85 g, 8.1 mmol), and potassium carbonate (K2CO3, 44.9 g, 320 mmol) in chloroform (CHCl3, 500 mL) was stirred mechanically at 40° C. for 1 h. Glycine methyl ester hydrochloride (10.2 g, 81 mmol) and K2CO3 (11.2 g, 80 mmol) were then added and stirred at 50° C. for 90 minutes (min). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2% methanol/ethyl acetate) to give the desired product as an orange gum which solidified upon standing at room temperature (4.7 g, 30%): 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=2.2 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.15 (dt, J=8.1, 1.8 Hz, 1H), 7.42 (dd, J=8.1, 4.8 Hz, 1H), 6.84 (br s, 1H), 4.28 (d, J=5.2 Hz, 2H), 3.87 (s, 3H); ESIMS m/z 195 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:12]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15]2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C@:24]1([CH3:30])[CH2:28][O:27]C(=O)[NH:25]1)=[CH:8]2.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][C@H:14]3[CH2:15][CH2:16][C@@H:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19]3)[C:3]=2[C:2]([F:31])([F:32])[F:1])[CH:8]=1)([CH3:30])[CH2:28][OH:27]
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Yield: 99.2 %

Procedure:
The mixture of (R)-4-(5-trifluoromethyl-6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (324.6 mg, 0.0007221 mol) and lithium hydroxide (190 mg, 0.0079 mol) in ethanol (10 mL, 0.2 mol) and water (3 mL, 0.1 mol) was heated to reflux for overnight. LCMS showed reaction completed. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product (303.5 mg, 99% yield). LCMS 407.28 ([M-NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.92 (t, J=6.8 Hz, 3H), 1.20-1.69 (m, 13H), 1.51 (s, 3H), 2.05 (dd, J=13.2, 2.3 Hz, 2 H), 3.66 (d, J=10.9 Hz, 1H), 3.73 (d, J=10.9 Hz, 1H), 4.83 (brs, 1H), 7.43 (d, J=9.4 Hz, 1H), 7.68 (dd, J=9.4, 2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 8.03 (d, J=9.4 Hz, 1H), 8.12 (dd, J=9.0, 1.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59]>>[C:58]([NH:57][CH2:56][CH2:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: COc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1ccccc1O
Product: COc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.090 g of tert-butyl 4-{4-[4-(2-methoxyphenoxy)butoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.048 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.48 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][OH:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>O1CCCC1.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
A mixture of 5-fluoro-2-(hydroxymethyl)benzoic acid (0.518 g, 3.04 mmol) and manganese(IV) oxide (3.71 g, 42.6 mmol) in tetrahydrofuran (25 mL) was stirred at room temperature for 16 hr. The insoluble material was removed by filtration through CELITE®. The filtrate was concentrated under vacuum to dryness. The residue was dissolved in CH2Cl2 (100 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.211 g, 1.255 mmol, 41.2% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]2)[C:11]=1[C:12]#[N:13]
Reactant: OCC1CCCCN1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OCC1CCCCN1

Procedure:
Prepared as in Example 24d from 2-piperidinemethanol and 2-amino-6-fluoro-benzonitrile as a light yellow solid (64%). MS 232 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:10](O)=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:19][C:10]1[C:9]([S:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:8])=[O:7])=[CH:14][N:13]=[C:12]([S:15][CH3:16])[N:11]=1
Reactant: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
N-(1,1-Dimethylethyl)-4-hydroxy-2-(methylthio)-5-pyrimidinesulfonamide (5.0 g, 18.05 mmol) and finely ground PCl5 (3.95 g, 18.95 mmol, 1.05 eq) were mixed as dry solids. Enough POCl3 was added to make a slurry (7 mL) and the mixture was warmed. The mixture loosened, turned more yellow, evolved a gas, and became homogeneous over a 10 minute period. The reaction was cooled to ambient temperature, diluted with methylene chloride and toluene and evaporated to dryness in vacuo to yield a pale yellow solid. The crude solid was crystallized from ethanol and water to give 3.8 g (12.86 mmoles, 71%) of pure product, m.p. 117°-118° C. as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cnccn1
Product: CCOC(=O)n1c(C(=O)c2cnccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-(bromoacetyl)pyrazine (prepared according to the method of F. H. Case et al., J. Am.Chem.Soc., 1956, 78, 5842).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=2)[CH:32]=[CH:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:42])=[CH:36][CH:37]=2)[CH:32]=[CH:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)CCCSc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1SCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
0.37 g of amorphous compound 51 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.30 g of ethyl 4-(2-aminophenylthio)butyrate and 1.0 g of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[OH2:13]>CS(C)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([CH:8]=[O:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: O
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CS(C)=O
Product: N#Cc1ccc(C(=O)C=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.1 %

Procedure:
A solution of 4-cyanophenacyl bromide (11.20 g, 49.99 mmol) in dimethylsulfoxide (83 mL) was treated with water (0.90 mL, 49.99 mmol). After stirring for 24 h at room temperature, it was poured into ice-water, and extracted with ether. The organic layer was washed with water and then brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting 20-50% ethyl acetate in hexane to afford 4-cyanophenylglyoxal (5.10 g, 64.1%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=O.[CH3:11][CH2:12][O:13][C:14]([CH3:16])=[O:15]>C1COCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:12][CH3:11])=[O:15]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triethyl phosphonoacetate (10.5 g, 47 mmol) in THF (100 mL) at 0° C. was added sodium hydride (2.2 g of a 60% suspension in mineral oil, 55 mmol) in portions over a period of 30 min, followed by pyridine 2-carboxaldehyde (5.0 g, 47 mmol). The resulting solution was stirred at 0° C. for 1 h and then at ambient temperature for 18 h. The solution was diluted with EtOAc and water. The organic phase was separated, washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 15-25% EtOAc:hexanes to give the title compound as a colorless liquid (6.0 g; TLC Rf=0.5, 1:2 EtOAc:hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2.P(Br)(Br)([Br:19])=O>>[Br:19][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc2ncc(Cl)c(O)c2c1
Reactant: O=P(Br)(Br)Br
Product: COC(=O)c1ccc2ncc(Cl)c(Br)c2c1
Temperature: 130 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of methyl 3-chloro-4-hydroxyquinoline-6-carboxylate (600 mg) and phosphoryl bromide (868 mg) was heated under stirring in an oil bath at 130° C. for 6 hours. Ice-water was added, followed by neutralization with saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain methyl 4-bromo-3-chloroquinoline-6-carboxylate (426 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (150 g, 544 mmol) in ethanol (750 mL), ammonium chloride (150 g, 2777 mmol) dissolved in water (750 mL) and iron powder (93.3 g, 1636 mmol) were added under stirring. Resulting reaction mass was heated at 80° C. for 7 h. On completion, reaction mass was filtered through celite giving washing of water and ethyl acetate, filtrate was extracted with ethyl acetate. Combined organic layers were dried, concentrated under reduced pressure giving the desired compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(O)(=O)[C:8]1[C:9](=C[CH:12]=[CH:13][CH:14]=1)[OH:10]>C1C=CC=CC=1>[OH:10][C:9]1[CH:8]=[CH:14][CH:13]=[CH:12][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1O

Procedure:
Add 11.8 g of oxalyl chloride dissolved in 25 ml of benzene to a suspension of 6.91 g of salicylic acid and 125 ml of benzene over a period of 20 minutes. Heat the mixture for about 14 hours, cool and evaporate the solvent to give 2-hydroxybenzenecarbonyl chloride as an oil. The crude product can be used directly in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54]([CH:59]([NH2:61])[CH3:60])=[CH:53]2.ClCCl.C(O)C.N.ClCl>O1CCCC1>[Cl:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54]([CH:59]([NH:61][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:60])=[CH:53]2
Reactant: CC(N)c1cc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(C)c2cc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 95 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-indol-2-yl)ethylamine in tetrahydrofuran. Yield: 95%; Rf value: 0.65 (silica gel: dichloromethane/ethanol/ammonia=9:1:0.1); C23H24ClN3O2 (409.915); mass spectrum: (M+H)+=410/412 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:6][CH:5]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[C:34]([C:32]([CH2:31][N:10]1[C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:6][CH:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1=[O:3])=[O:33])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
60% Sodium hydride (53 mg) was suspended in anhydrous N,N-dimethylformamide (5 ml), under ice-cooling 2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (410 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, bromomethyl-tert-butyl ketone (217 mg) was added to the mixture under ice-cooling, the mixture was stirred at room temperature for 30 minutes. Ice-water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby 517 mg of the title compound (Yield: 100%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].F>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
The product from Step 4A (500 mg) was dissolved in acetonitrile (20 ml) and 100 ml of hydrogen fluoride (48%) was added. The reaction was stirred for 20 minutes at room temperature, quenched with saturated sodium bicarbonate, then extracted with ethyl acetate. Removal of solvent in vacuo followed by chromatography on silica gel (80% ethyl acetate/hexane) gave 300 mg of product (Mass, 1 H and 13C NMR data consistent with the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 5 h
Yield: 17.3 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) (103 mg, 0.26 mmol) in dioxane (5 mL) at room temperature (20° C.) was added methyl chloroformate (32 uL, 0.23 mmol). The reaction mixture was stirred for 5 h. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford an orange solid (18 mg, 15%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].N1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[OH-].[Na+].[NH2:32][C@H:33]([C:39]([OH:41])=[O:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>C1COCC1.O>[NH2:32][C@H:33]([C:39]([OH:41])=[O:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: CN(C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of benzyl chloroformate (7.3 mL, 51.9 mmol) in THF (70 mL) was treated with benzotriazole (6.1 g, 51.2 mmol) and dimethylaminopyridine (83 mg, 0.68 mmol). The mixture was stirred at room temperature for 4 hours, while maintaining pH 10 with aqueous sodium hydroxide, and a thin suspension was obtained. This mixture was slowly poured, stirring at 0° C. and maintaining pH 12 with aqueous sodium hydroxide, into a solution of L-lysine (5.0 g, 34.2 mmol) in water (75 mL) at pH 12. After adding further 50 mL of THF and 50 mL of water, the reaction mixture was stirred overnight, then partly concentrated under vacuum and treated with hydrochloric acid to pH 5.6. The suspension was filtered and the residue washed 3 times with chloroform. The product (7.3 g, 76%) is the expected H-Lys(Z)-OH (1H-NMR, 13C-NMR, ESI-MS).