Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=O>>[O:31]1[C:30]2[CH:35]=[CH:36][C:27]([C:25]3[N:12]=[C:11]([C:9]4[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=4)[S:13][CH:24]=3)=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Product: O=C(O)c1cc(-c2nc(-c3ccc4c(c3)OCCO4)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (205 mg, 71%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethan-1-one (available from Alfa Aesar) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=1.8 Hz, 2H), 8.24 (dd, J=8.0, 1.9 Hz, 1H), 8.11-8.16 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.52-7.68 (m, 3H), 7.43 (t, J=8.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 1H), 4.29 (s, 4H).
Reaction SMILES: C([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:28]([O:27][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)OC)cc2)cc1)C(=O)O
Yield: 97.1 %

Procedure:
(S)-2-Ethoxy-3-(4-[2-{4-(methoxycarbonylamino)phenyl]ethoxy]phenyl)propanoic acid ethyl ester (described in Example 41) (0.52 g; 1.25 mmole) was dissolved in tetrahydrofuran (10 ml) and lithium hydroxide (0.034 g; 1.42 mmole) dissolved in water (2 ml) was added slowly. The reaction mixture was stirred over night, hydrochloric acid (1 M, 1 ml) was added and tetrahydrofuran evaporated. The residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated and 0.47 g (99% yield) (S)-2-ethoxy-3-[4-{2-[4-(methoxycarbonylamino)phenyl)ethoxy]phenyl}propanoic acid was obtained.
Reaction SMILES: C([SiH](CC)CC)C.O[C:9]1([C:25]2[C:35]([OH:36])=[CH:34][C:28]3[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)[C:10]1=[O:24].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[OH:36][C:35]1[C:25]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[C:10]2=[O:24])=[CH:26][C:27]2[O:32][CH2:31][CH2:30][N:29]([CH3:33])[C:28]=2[CH:34]=1
Reactant: CN1CCOc2cc(C3(O)C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCOc2cc(C3C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of triethylsilane (1.3 mL, 8.2 mmol) in trifluoroacetic acid (8 mL) was added dropwise a solution of 3-hydroxy-3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one (1.04 g, 2.62 mmol) in dichloromethane (3 mL). The resulting solution was warmed to reflux and stirred under nitrogen for 90 min. Once cooled, the solvent was removed under reduced pressure to afford 3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one trifluoroacetate as a light brown foam: MS (ES+) m/z 381.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[OH:23][CH2:24][C:25]([NH:27][NH2:28])=O>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:25]([CH2:24][OH:23])=[N:27][N:28]=[C:12]3[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CO)n1-2

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-7-nitro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butylalcohol was refluxed to give 8-nitro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=1
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1
Yield: 49.4 %

Procedure:
The reaction of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine with 1-amino-2,2-dimethylpropane as described in Example 10 affords the title product in a yield of 49.4%, m.p.: 95°-98° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[C:7](Cl)(=O)[CH2:8][CH3:9].C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([CH2:8][CH3:9])[O:6][N:5]=1
Reactant: CCC(=O)Cl
Reactant: N=C(CCl)NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc(CCl)no1
Temperature: 130 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
2.0 g of 2-chloro-N-hydroxyacetoamidine and 1.80 g of propionyl chloride were dissolved in 50 ml of N,N-dimethylformamide, and 2.05 g of triethylamine was added dropwise under ice-cooling. The mixture was stirred at 130° C. for 5 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.62 g of 3-(chloromethyl)-5-ethyl-1,2,4-oxadiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>O1CCCC1.[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cc(F)cc(F)c1
Yield: 98.8 %

Procedure:
A solution of 3-(3,5-difluorophenyl)propenoic acid (0.0435 mol) in tetrahydrofuran (100 ml) and a slurry of 10% palladium on carbon (1.5 g) in ethyl acetate were shaken together under 50 psi hydrogen for 4 hours. The mixture was filtered and concentrated to yield 8 g (99%) of a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:3]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[CH:10][CH:11]=2)[N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(SC)c2ccc(Cl)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm;
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH3:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12].[CH2:15]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:9][N:10]([CH3:14])[C:11](=[O:13])[CH2:12][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CC(=O)N(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)CC(O)(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred ice-cold (0° C.) solution of 10 g (0.1 mole) diisopropylamine in 100 ml of anhydrous THF under nitrogen gas is added, dropwise, 40 ml (2.5 M) n-butyllithium over a period of about 15 min to form lithium diisopropylamine solution, which is a pale yellow. To the amine solution is added 8.8 g (0.1 mole) N,N-dimethylacetamide in 10 ml THF, dropwise, via syringe, over a period of 10 min. The resulting lithium enolate of N,N-dimethylacetamide solution is deep yellow, and is stirred for 45 min at 0° C. A solution of 18.5 g (0.095 mole) benzylphenylketone in 20 ml of THF is added rapidly over a period of about 2 min to the enolate solution. An orange N,N-dimethyl-3,4-diphenyl-3-hyroxybutyramide solution is formed, and is stirred at 0° C. for about 15 min. Then 40 ml (2.5 M) n-butyllithium is added dropwise via syringe to form a deep red dianion solution. The dianion solution is stirred at about -20° C. for 30 min. Methyl bromide (19 g, 0.2 mole, 2 equivalents) in 20 ml THF is added slowly to methylate the dianion. The resulting N,N-dimethyl-2-methyl-3,4-diphenyl-3-hydroxybutyramide mixture is held at about -20° C. for about 1 h, and a cloudy yellow suspension is formed. The suspension is warmed to room temperature (25° C.), then quenched with 200 ml of a 0° C. solution of 2 N HCl, which is added with rapid stirring. The quenched, pale yellow solution is diluted with 200 ml ether. The organic layer is recovered and washed with brine and dried over anhydrous MgSO4. The mixture is filtered, yielding a pale yellow solution of N,N-dimethyl-2-methyl-3,4-diphenyl-3-hydroxybutyramide, which is reduced in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][OH:24])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][O:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(3-methoxycarbonylpropyl)propanamide (504 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (497.8 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=[C:7]([CH3:14])[CH:6]=1>CO>[CH3:1][O:2][C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=[C:7]([CH3:14])[CH:6]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)n2ncnc2n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc2ncnn12
Reaction time: 0.5 h

Procedure:
A 28% methanol solution of sodium methoxide, 2.52 g, is diluted with 50 ml of dry methanol To this, 2.00 g of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine is added at room temperature and stirred for 30 minutes. The solvent is evaporated under reduced pressure and the residue is treated with water and extracted twice with dichloromethane. The combined extract is washed with saline and dried over anhydrous potassium carbonate. Evaporation of the solvent under reduced pressure gives 1.69 g of the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:14][N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(F)c(Cl)c1
Yield: 66.9 %

Procedure:
Using the same reaction procedure and workup as described in Example 1, 3-chloro-4-fluoro-benzaldehyde (2 g, 12.6135 mmol) in ethanol (63 mL) was reacted with nitro methane (0.68 mL, 12.6135 mmol), 10N NaOH solution (529.7 mL, 13.2441 mmol) at 0° C. for 1 hr to afford 1.7 g of the product (67.05% yield).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:25]1([P:31]([O-:35])[O:32][CH2:33][CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:33]([O:32][P:31]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:35])[CH3:34]
Reactant: C=C1CC(=O)O1
Reactant: CCOP([O-])c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOP(=O)(CC1CC(=O)O1)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 8.4 parts of diketene, 2.5 parts of benzoyl peroxide and 20.0 parts of ethyl phenylphosponite were added dropwise over 1 hr to 48.1 parts of vigorously stirred ethyl phenylphosphonite which was heated at 120° C. in an atmosphere of nitrogen. The excess phosphonite was removed by passing the reaction mixture down a wiped wall still at 80° C. at a pressure of 0.013 mb. The residue was distilled on a wiped wall still at a temperature of 110° C. and a pressure of 0.013 mb and the product, ethyl(2-oxo-4-oxetanylmethyl)phenylphosphinate, was obtained as a colourless oil which was shown by 31P NMR to be a nearly equal mixture of diastereoisomers having chemical shifts at δ-37.5 and δ-37.7 and which had the following elemental analysis by weight.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:2][C:3]2[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=2)[CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of N-(3-aminobenzyl)-3-nitrobenzamide hydrochloride (0.70 g, 2.3 mmol) and 2,4,5-trichloropyrimidine (0.237 mL, 2.07 mmol) in DMF (5.5 mL) was added potassium carbonate (1.0 g, 7.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give 1.25 grams of crude material, which was triturated with MeOH/EtOAc to give the desired product as an off-white powder (665 mg, 77%). LCMS for C18H13Cl2N5O3 (M+H)+: m/z=418.0, 420.0, 422.0. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.49 (t, J=2.0 Hz, 1H), 8.74 (t, J=2.0 Hz, 1H), 8.36 (m, 3H), 7.78 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.15 (d, J=8.0, 1H), 4.52 (d, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 77.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 47 (61 mg, yield 77.7%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:18]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1)(O)=[O:19].C(P(=O)(OCC)OCC)#N>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=2)=[O:19])=[C:3]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:4]=1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A mixture of t-butyl N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate (0.43 g), 5-(4-carboxymethoxybenzyl)thiazolidine-2,4-dione (0.51 g), diethyl cyanophosphonate (0.29 g) triethylamine (0.18 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 8 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=2:3 as the eluant to afford t-butyl N-{5-hydroxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl) phenoxymethylcarbonylamino]phenyl}-N-methylcarbamate (0.75 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].O[CH:42]([C@@H:68]1[CH2:72][C@H:71]([SH:73])[CH2:70][N:69]1[C:74]([O:76][CH2:77][C:78]1[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=1)=[O:75])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@H:48]([NH:51][C:52](=[NH:67])[CH2:53][C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=2)=[O:55])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:73][C@@H:71]3[CH2:70][N:69]([C:74]([O:76][CH2:77][C:78]4[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=4)=[O:75])[C@@H:68]([CH2:42][CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([NH:51][C:52](=[NH:67])[CH2:53][C:54]([O:56][CH2:57][C:58]5[CH:59]=[CH:60][C:61]([N+:64]([O-:66])=[O:65])=[CH:62][CH:63]=5)=[O:55])[CH2:47]4)=[O:45])[CH2:72]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](CCC(=O)N4CC[C@H](NC(=N)CC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 73.3 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (563.2 mg) and (2S,4S)-2-[1-hydroxy-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylamino)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (594.3 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylamino)pyrrolidin-1-ylcarbonyl]ethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (653.2 mg) was obtained as an amorphous substance.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCCC1CCNCC1
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.063 g, 0.19 mmol) and 4-butyl-piperidine (0.053 g, 0.38 mmol) in MeCN (12 mL) were reacted according to GP10 shaking at 50° C. for 1 day and at 70° C. for 2 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50) to give the title compound (108LM22-20) (0.051 g, 79%). 1H NMR (CDCl3) δ 7.18-7.15 (m, 1H), 7.02-6.96 (m, 3H), 4.60 (ABq, J=15.0 Hz, J=31.3 Hz, CH2), 3.99 (dd, J=8.1 Hz, 13.8 Hz, 1H), 3.92 (dd, J=5.0 Hz, 13.8 Hz, 1H), 2.88 (bd, J=10.0 Hz, 1H), 2.72 (bd, J=10.0 Hz, 1H), 2.26-2.02 (m, 3H), 2.00-1.92 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.59 (m, 2H), 1.32-1.14 (m, 9H), 0.92-0.85 (m, 6H); HPLC-MS (ammonium acetate) [M+H]+=345.3.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Brc1cccnc1
Product: COc1ccc(-c2cccnc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (500 mg, 1.27 mmol) is coupled to 3-bromopyridine (202 mg, 1.27 mmol) using Method A to afford the title compound.