Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 89 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 2.45 (s, 3H), 3.45-3.60 (m, 4H), 3.76-3.88 (m, 4H), 4.09 (s, 3H), 6.85 (d, J=6.2 Hz, 2H), 7.03-7.68 (m, 4H), 8.16 (d, J=6.0 Hz, 2H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)C.Cl>CO>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][CH2:25][N:17]([CH2:16][CH2:15][CH2:14][O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:33])=[O:5])[CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:28]=1
Reactant: CCOC(=O)c1ccccc1OCCCN(CCc1cccnc1)Cc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1OCCCN(CCc1cccnc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
A 1N-sodium hydroxide aqueous solution(1.8 ml) was added to a methanol solution (3 ml) of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester(372 mg). The mixture was stirred at room temperature overnight. 6N-Hydrochloric acid(0.3 ml) was added to the reaction mixture and condensed under reduced pressure. Methanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound(458 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH:11]1O[CH:14]=[N:13][CH:12]1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:10].[NH3:26]>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:9]([C:11]2[N:26]=[CH:14][NH:13][CH:12]=2)[CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C2N=COC2C(C)c2cccc(C)c2C)cc1
Reactant: N
Product: Cc1cccc(C(C)c2c[nH]cn2)c1C
Temperature: 110 °C
Yield: 88.7 %

Procedure:
Compound of formula (23) (3.16 g, 8.84 mmol), prepared according to example 4, was dissolved in ammonia-saturated ethanol (40 ml, containing approximately 160 mmol ammonia) and heated to 110° C. for 3 h. The mixture was then evaporated to dryness, and the residue was mixed with an aqueous, saturated solution of NaHCO3 (20 ml). The mixture was extracted with toluene (2×20 ml), and the combined extracts were washed with water (2×20 ml). The combined extracts were then extracted with 10% aqueous HCl (3×20 ml), and the combined acidic extracts were basified with gaseous ammonia, and extracted with toluene (2×20 ml). The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure, to yield compound of formula (XX) (1.57 g, 89%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CCl
Yield: 88.6 %

Procedure:
Into a 500-mL autoclave was introduced [{RuCl((R)-SEGPHOS)}2(μ-Cl)3][Me2NH2] (122 mg: 0.149 mmol). After the atmosphere in the autoclave was replaced with nitrogen, distilled ethanol (183 mL) and ethyl 4-chloroacetoacetate (60.9 g: 0.37 mol) were added thereto. The autoclave was heated until the temperature of the contents reached 90° C. and hydrogen (3.0 MPa) was forced into the autoclave to react the reaction mixture for 2 hours, during which the hydrogen pressure of 3.0 MPa was maintained. After completion of the reaction, the solvent was removed and the residue was distilled under reduced pressure to obtain ethyl (S)-4-chloro-3-hydroxybutanoate (54.6 g: yield, 88.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])([O-:3])=[O:2].C1C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:25])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Fifty-three grams (0.25 mole) of 3,4-dinitrobenzoic acid, 500 ml. of benzene, 65 g. (0.51 mole) of oxalyl chloride and 1 ml. of pyridine were reacted according to Example 6 (A), first paragraph, to provide 3,4-dinitrobenzoyl chloride as a crude oil.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17](=[O:48])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19].[Na]>O>[NH2:16][C:17](=[O:48])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([O:33][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19]
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OCCN3CCOCC3)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
In a flask containing 10 ml of dimethylformamide was added with stirring 133 mg. of 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3) and 231 mg. of CsCO3 and 300 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The slurry was heated to 60° C. until a solution formed. Heating was continued overnight until reaction was complete. 20 ml of H2O was added to the flask and the organic soluble phase extracted with three 20 ml. portions of ethyl acetate. The ethyl acetate solution was washed with water and dried over and dried over Na2SO4. Removal of solvent gave product verified by IR and NMR to be the title compound. Molecular Formula: C32H22N3O6
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCO
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 4-aminobutanol to produce [2-(4-hydroxybutyl]amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(4-hydroxybutyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 4-(3,5-dioxomorpholino)butyl methanesulfonate and (d) reacting the mesylate with 3[bis(4-butoxy-o-tolyl)methyl]piperidine.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9]Cl)(=[O:4])[CH2:2][CH3:3].C1N2CN3CN(C2)CN1C3.C1N2S(=O)(=O)N3CN(C2)S(=O)(=[O:29])N1C3.ClCCCl>O>[C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH:9]=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCC=C(C)CCl
Reactant: O=S1(=O)N2CN3CN1CN(C2)S3(=O)=O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCCl
Solvent: O
Product: CCC(=O)OCC=C(C)C=O
Temperature: 35 °C
Reaction time: 4 h
Yield: 26.8 %

Procedure:
The crude 4-propionyloxy-2-methyl-1-chloro-2-butene (64.0 g, 0.362 mol) obtained in the above (i) was added to a solution of hexamethylenetetramine (50.9 g, 0.363 mol) in water (345 ml), and the mixture was stirred at 35° C. for 4 hours to prepare a tetramine salt. 1,2-Dichloroethane (200 ml) was added to the reaction mixture, and compounds insoluble in water were removed by extraction. 1,2-Dichloroethane (400 ml) was further added to the aqueous layer that had been washed, and the mixture was stirred at 60° C. for 4 hours to hydrolyze the tetramine salt. After completion of the reaction, the 1,2-dichloroethane layer was separated, and 1,2-dichloroethane (250 ml) was further added to the aqueous layer for extraction. The 1,2-dichloroethane layers were combined and dried over anhydrous sodium sulfate. The 1,2-dichloroethane was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane (=1:5)) to give 4-propionyloxy-2-methyl-2-buten-1-al (15.2 g, 0.0973 mol, Yield: 26.8% ).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH:28]4[CH2:30][CH2:29]4)=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:31][C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH:28]1([C:24]2[CH:25]=[C:26]([CH3:27])[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:13]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[C@H:32]([CH3:31])[CH2:36][O:35][C:34]5=[O:37])=[CH:7][C:6]=4[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]3)=[N:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2NS(C)(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2NS(C)(=O)=O)CC1
Yield: 14 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using N-{5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (247 mg) described in Preparation Example 124 and (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, the title compound (35.9 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2ccc(N)cc2F)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.5 %

Procedure:
3-Fluoro4-(4-methyl-imidazol-1-yl)nitrobenzene (64.7 g, 0.293 M) was dissolved in a mixture of MeOH (200 ml) and tetrahydrofuran (800 ml), cooled to 0° under nitrogen, and treated with ammonium formate (99.3 g, 1.46 M) followed by palladium on charcoal (10%. 2.5 g). The mixture was stirred at ambient temperature for 48 hours, filtered through celite, celite washed with MeOH (200 ml), and filtrate evaporated to dryness. The residue was partitioned between EtOAc (800 ml) and 10% aqueous sodium bicarbonate (250 ml). The organic layer was separated, washed with brine (250 ml), dried (magnesium sulfate) and evaporated to give title compound (50.6 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M83) (0.53 g, 0.83 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a off-white solid (120 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[C:4](Cl)[N:3]=1.C(O)=[O:20]>>[OH:17][CH2:16][CH2:15][CH:12]([CH2:13][OH:14])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(Cl)c2ncn(CC(CO)CCO)c2n1
Reactant: O=CO
Product: Nc1nc2c(ncn2CC(CO)CCO)c(=O)[nH]1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A solution of (-)-2-(2-amino-6-chlorpurin-9-ylmethyl)-1,4-butanediol (11.5 mg, 0.0423 mmol) in 50% aqueous formic acid (0.75 ml) was kept at 100° C./2 h and then evaporated to dryness, dissolved in 2 ml of water and lyophilized. The product was dissolved in 1 ml of water, 2 drops of conc. aqueous ammonia was added and the solution kept at 100° C. for 10 min, flushed with nitrogen to remove ammonia, and lyophilized. The residue was dissolved by warming with 1.2 ml of 20% aqueous methanol and the solution filtered and kept in open air to allow for slow partial evaporization of solvent. Crystalline needles were formed. Filtration, washing with 3 drops of water and drying yielded 6.4 mg (60%) of (-)-9-(4-hydroxy-2-hydroxymethylbutyl)guanine.
Reaction SMILES: C1C=CC(C(Cl)([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][CH:15]=2)C2C=CC=CC=2)=CC=1.I[C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([C:35]([OH:37])=[O:36])[O:32][C:33]=2[CH3:34])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:20][C:19]1[CH:14]=[CH:15][C:16]([C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]([OH:37])=[O:36])[O:32][C:33]=3[CH3:34])=[CH:25][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.8 %

Procedure:
2-Chlorotrityl chloride resin (2.55 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.18 g) and diisopropylethylamine (2.3 mL) in dichloromethane (30 mL) was added and the mixture was shaken at room temperature for 72 hours. The resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3×30 mL), dichloromethane (6×30 mL), N,N-dimethylformamide (2×25 mL), dichloromethane (6×25 mL), and diethyl ether (2×25 mL) and dried at 40° C. in vacuo, (ii) A stirred mixture of the resin from (i) (0.38 g), 4-chlorophenylboronic acid (0.30 g), [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg), potassium acetate (0.20 g) in N,N-dimethylformamide (15 mL) was heated at 40° C. for 48 hours. The resin was drained, then washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether and then dried at 45° C. in vacuo. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by HPLC to afford compound 27 as a white solid (43 mg). LC/MS System D: Rt=8.83 mins, m/z (ES−)=341 (M− for C19H15ClO4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:16].C[Si]([N:21]=[N+:22]=[N-:23])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[Br:16][C:3]1[CH:4]=[C:5]([C:8]2([C:14]3[N:21]=[N:22][NH:23][N:15]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC1(c2ccc(N)c(Br)c2)CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2(c3nn[nH]n3)CCOCC2)cc1Br
Temperature: 120 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A mixture of 4-(4-amino-3-bromo-phenyl)-tetrahydro-pyran-4-carbonitrile (as prepared in the previous step, 141 mg, 0.500 mmol), trimethylsilylazide (133 μL, 1.00 mmol) and tetrabutylammonium fluoride (65 mg, 0.25 mmol) was stirred at 120° C. for 18 h under Ar. After cooling to RT, the mixture was treated with 30 mL of EtOAc and washed with H2O (2×10 mL), 15% citric acid aqueous solution (3×10 mL) and brine (10 mL). After drying over Na2SO4, the organic layer was concentrated in vacuo to afford the title compound (147 mg, 91%) as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C12H14BrN5O, 324.0 (M+H). found 324.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=2[NH:6][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([N:6]1[C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[NH:3][C:2]([CH3:1])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=C(C)Nc2ccccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)Nc2ccccc2N(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester (800 mg., 2.36 mmole) in dichloromethane (8 ml.) is treated with pyridine (280 mg., 3.53 mmole), acetic anhydride (479 mg., 4.72 mmole) and 4-dimethylaminopyridine (5 mg.). The reaction is stirred at room temperature for 16 hours. A light yellow solid precipitates out of the reaction. The reaction is diluted with dichloromethane/methanol (100 ml. of 95:5 mixture) and the resulting solution is washed with 10% citric acid, 5% sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate, the solvent is evaporated to give a yellow foam. This foam is triturated with ether to give 705 mg. of yellow crystals. Recrystallization from dichloromethane-methanol-isopropanol gives an analytically pure sample of 1-acetyl-2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester as yellow crystals; m.p. 231°-232.5°. TLC(silica gel; acetone:hexane, 40:60) Rf = 0.28.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:9][C:8]=1[O:22][C:23]([F:26])([F:25])[F:24]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[CH2:1])=[CH:14][CH:13]=2)=[CH:9][C:8]=1[O:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.9 g, 10.92 mmol) in dry THF (20 mL) was added n-butyllithium (6.8 mL, 10.88 mmol) dropwise at −78° C. for 0.5 h, the mixture was stirred for 1 h, and then was added a solution of 4-(4-chloro-3-(trifluoromethoxy)phenoxy)benzaldehyde (2.8 g, 8.84 mmol) in THF (5 mL). The reaction was warmed slowly to room temperature, stirred for overnight, and quenched with water. The aqueous layer was extracted with DCM. The organic phase was dried with anhydrous Na2SO4, concentrated and purified via flash chromatography to afford the title compound (1.2 g, 3.81 mmol, 43.1% yield). LCMS: rt=4.42 min, [M+H+]=315
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:42][O:43][CH3:44])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][CH:34]=[C:35]3[C:39]([O-:41])=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].C(O)=O>O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:42][O:43][CH3:44])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][CH:34]=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CSCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CSCC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The 297 mg of the product of Step A were suspended in 1.5 ml of aqueous 66% formic acid solution and the mixture was stirred at 50° C. for 15 minutes and was then cooled to room temperature. 0.66 ml of water were added to the mixture which was then filtered and the filter was rinsed with water. A little ethanol was added to the filtrate which was then evaporated to dryness under reduced pressure. The oil residue was taken up in water and ethanol and the mixture was again evaporated to dryness. The residue was added to 2 ml of a 1 M solution of sodium bicarbonate solution and 1.65 ml of water to form a solution which was then filtered. 2 N hydrochloric acid was added to the mixture to adjust the pH to 3 and a little ethanol was added thereto. After crystallization, the mixture was filtered and the product was rinsed with water and then with ether and dried to obtain 102 mg of syn isomer of (6RS, 7RS) 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH2:32]([O:34][C:35](=[O:40])[C:36](Br)([CH3:38])[CH3:37])[CH3:33]>CCCCCCC.C(OCC)(=O)C>[CH2:32]([O:34][C:35](=[O:40])[C:36]([O:30][C:26]1[CH:25]=[C:24]([Cl:31])[C:23]([O:22][C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][CH2:6]2)=[O:15])=[CH:28][C:27]=1[Cl:29])([CH3:38])[CH3:37])[CH3:33]
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 58, from (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) and 2-bromo-2-methyl-propionic acid ethyl ester (commercially available, CAS RN 600-00-0) after a reaction time of 23 hours at room temperature and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light brown foam (30%). MS (ESI): m/z=570.156 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C@@H:8]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:2].Cl.[NH2:22][OH:23].CCN(CC)CC>CCO>[OH:23][NH:22][C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C@@H:8]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C#N)cccc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C(=N)NO)cccc21
Temperature: 85 °C

Procedure:
Prepared using General Procedure 1. To a stirring solution of (S)-tert-butyl (5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-8 (3.10 g, 11.38 mmol) in EtOH (25 mL) was added hydroxylamine hydrochloride (2.77 g, 39.84 mmol) and NEt3 (3.17 mL, 22.77 mmol). After heating at 85° C. for 15 h, the mixture was concentrated, redissolved in DCM, and washed with NaHCO3. The combined organic layers were dried, concentrated and chromatographed (MeOH/DCM) to provide 3.56 g crude (S)-tert-butyl (5-(N-hydroxycarbamimidoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-10 (58% product by UV area), which was used in the next reaction without further purification. LCMS-ESI (m/z) calculated for C16H23N3O3: 305.37; found 306.2 [M+H]+, tR=2.00 min.