Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([O:28]CC)=[O:27])=[CH:3]1.C(=O)(O)[O-].[Na+]>C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([OH:28])=[O:27])=[CH:3]1
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A solution of 2.05 parts of ethyl 4-oxo-7-(3-[2-propylphenoxy]-propoxy)- 4H-1-benzopyran-2-carboxylate and 0.46 parts of sodium bicarbonate in 100 parts of 50% v/v aqueous ethanol was stirred on a steam bath for three hours, then cooled and extracted with ether. The aqueous extract was acidified with excess 2N hydrochloric acid to give a white precipitate which was collected, washed with water and dried. Crystallisation of this solid from acetone gave 1.01 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 168°-171°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([NH:14][C@H:15]([C:20](=[O:23])NC)C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.N[C@H](CO)[CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:12]([NH:14][C@@H:15]([CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1)[CH2:20][OH:23])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](CO)Cc1c[nH]cn1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]cn1
Yield: 92 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartic acid β-benzyl ester and L-histidinol dihydrochloride were coupled with TBTU to furnish 410 mg(92%) of 3(R)-(t-butoxycarbonylamino)-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester as a solid which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[S:9]1(=[O:48])[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[CH:22]=[C:23]([C:33]([NH:35][C:36]4[CH:40]=[CH:39][N:38](C(OC(C)(C)C)=O)[N:37]=4)=[O:34])[CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][NH:10]1>C(Cl)Cl>[O:48]=[S:9]1(=[O:8])[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[C:33]([NH:35][C:36]3[CH:40]=[CH:39][NH:38][N:37]=3)=[O:34])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][NH:10]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 1,1-dimethylethyl 3-{[(3-[(1,1-dioxido-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate (47 mg, 0.08 mmol) in DCM (8 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (39 mg).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([N:14]1[CH2:33][CH2:32][CH2:31][C@H:15]1[C:16]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC([O:43][C:44](=O)[C@H:45]([CH2:57][C:58](=[O:60])[NH2:59])[NH:46]C(OCC2C=CC=CC=2)=O)=CC=1)([O-])=O.CN(C)C=O>C(OCC)(=O)C>[NH2:46][C@H:45]([C:44]([NH:11][C@H:10]([C:12]([N:14]1[CH2:33][CH2:32][CH2:31][C@H:15]1[C:16]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[O:13])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:43])[CH2:57][C:58](=[O:60])[NH2:59]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CSCc1ccccc1)C(=O)NCC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CSCc1ccccc1)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of S-benzyl-L-cysteinyl-L-prolyl-L-leucyl-glycinamide (0.502 g.) in ethyl acetate (3 ml.) benzyloxycarbonyl-L-asparagine p-nitrophenyl ester (0.387 g., 1.0 mmol) was added and the suspension stirred at room temperature for 48 hr. The precipitate which formed was collected by filtration and washed with ethyl acetate (20 ml.) and ethanol (5 ml.), and then dried. The crude benzyloxycarbonyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-L-leucyl-glycinamide was recrystallized from 40% methanol. Yield, 0.718 g. (99%); m.p. 212°- 213.5°; [α]20D -60.5° (c 1, dimethylformamide).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>[OH-].[Li+]>[NH2:2][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N[C@@H](CCCCN=Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
L-lysine, monohydrochloride (130 g.) is dissolved in 2N lithium hydroxide (360 ml.) solution in a 2-liter, 3-necked, round bottom flask, equipped with an overhead stirrer, addition funnel and thermometer. Benzaldehyde (76.4 ml.) is added dropwise to this vigorously stirring solution at a temperature of about 5°. The reaction mixture turns cloudy at first and then becomes a thick mass of white precipitate. The rest of the benzaldehyde is added along with toluene (300 ml.) to improve the difficult stirring. The reaction mixture is stirred at about 5° for three hours. The mixture is filtered in a coarse sintered glass funnel. The solid is washed with ice cold water (50 ml.), ice cold ethanol (2×115 ml.), and then extensively with anhydrous ether. The product is dried in vacuo over 16 hours to give (S)-2-amino-6-[(benzylidene)amino]hexanoic acid as a white powder; m.p. 196°-200°.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][C:16]([O:18][C:19](C)(C)[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A round-bottom flask was charged with 2,3-dinitrophenol (11.04 g, 60 mmol, commercially available from Fluka-Sigma-Aldrich), tert-butyl bromoacetate (14.05 g, 66 mmol), acetonitrile (120 mL) and cesium carbonate (21.6 g). The mixture was stirred at room temperature overnight. The mixture was filtered, and the recovered solid was washed with ethyl acetate. The filtrate was further diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and combined organic solvent was washed with saturated brine, dried and concentrated under reduced pressure. The residue was triturated with ether to give ethyl 2-(2,3-dinitrophenoxy)acetate (13.0 g, 70% yield). 1H-NMR (DMSO-d6) δ 7.84 (d, 2H), 7.42 (s, 1H), 4.90 (s, 2H), 1.40 (S, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:25]([CH3:27])[CH3:26])[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:5])C.Cl>C(O)C.[OH-].[Na+]>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:8][N:7]([CH:25]([CH3:27])[CH3:26])[C:6]=2[C:4]([OH:5])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c(-c2ccc(F)cc2)cn1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1C(=O)O

Procedure:
6.8 g (18.4 mol) of the compound from Example 3 are heated to reflux for 18 hours in 30 ml of ethanol and 3.4 ml of 6N sodium hydroxide solution. The mixture is then acidified using 1N hydrochloric acid and the deposited precipitate is filtered off with suction. The precipitate is dissolved again in ethyl acetate, extracted using 1N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness. Recrystallization from ether/petroleum ether yields 4.35 g (69% of theory) of colorless crystals of melting point 212° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C@@:9]1([CH3:18])[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C@@:9]1([CH3:18])[C:15]([O:17][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@]1(C(=O)O)COCC(=O)N1Cc1ccccc1
Product: C[C@@]1(C(=O)OCc2ccccc2)COCC(=O)N1Cc1ccccc1
Yield: 70.1 %

Procedure:
(S)-4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid (2.49 g, 10 mmol) was reacted with benzyl bromide (2.05 g, 12 mmol) according to the procedure as described in Example 34, Step A to give the title compound as colorless oil (2.38 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7](O)[CH2:6][C@H:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].CS(Cl)(=O)=O>ClCCl.C(N(CC)CC)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)C[C@H]1c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C=CC1c1ccccc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
6.0 g (17.9 mmol) of rel-(7S,9S)-10-acetyl-7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (racemic) are dissolved in 100 ml of dichloromethane and 20 ml of triethylamine. A solution of 2.9 g (25 mmol) of methanesulphonyl chloride in 5 ml of dichloromethane is then added dropwise with ice cooling within 30 min. After 2 h, hydrolysis is effected using water and extraction using dichloromethane. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether. 4.8 g (85%) of the title compound are isolated as a pale brown solid (m.p. 170° C.).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.O1CCCC1.C1([Li])C=CC=CC=1.[Br:29][CH2:30][CH2:31][CH2:32]Br>C1CCCCC1>[S:1]1[C:5]([CH:6]=[CH:7][C:8]2[S:9][C:10]([CH2:32][CH2:31][CH2:30][Br:29])=[CH:11][CH:12]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: BrCCCBr
Reactant: C(=Cc1cc2ccccc2s1)c1cccs1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: BrCCCc1ccc(C=Cc2cc3ccccc3s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred, chilled (-65° C.) solution of 2-[2-(benzo[b]thiophen-2-yl)-ethenyl]thiophene (8.1 g) and tetrahydrofuran (100 ml) was added over 15 mins phenyl lithium (18 ml of a 2.0M solution in cyclohexane). The mixture was stirred for 1 hr, and 1,3-dibromopropane (40.5 g) was added. The solution was allowed to warm to room temperature, and was refluxed overnight. The reaction mixture was quenched with methanol (30 ml) and water (100 ml). The organic phase was evaporated in vacuo, and the residue was extracted with dichloromethane. The combined, dried over anhydrous sodium sulfate organic phase was concentrated. The residue was purified by high pressure liquid chromatography (silica gel, eluted with 7:1 hexane: dichloromethane). The appropriate fractions were combined and evaporated to yield 2.15 g (18%) of product, mp 109°-111° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([OH:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:15][CH3:16]>>[CH2:15]([O:12][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11])[CH3:16]
Reactant: O=C(O)c1cc(F)c(O)c(F)c1F
Reactant: CCI
Product: CCOc1c(F)cc(C(=O)O)c(F)c1F

Procedure:
Using 2,3,5-trifluoro-4-hydroxybenzoic acid and iodoethane, and in the same manner as in Step A of Example 39, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:26]3[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=3)=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)cn1
Yield: 42 %

Procedure:
1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (500 mg) was reacted with 2-methoxypyrimidine-5-boronic acid as in General Procedure 4A to give the title compound as a pale orange foam in 42% yield. M.p. (foam), LCMS: m/z=404.36 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.51 (t, J=5.3 Hz, 2H), 3.66-3.70 (m, 2H), 4.01 (s, 3H), 4.49 (s, 2H), 4.99 (bs, 1H), 6.46 (d, J=1.5 Hz, 1H), 7.18-7.26 (m, 2H), 7.35 (d, J=8.3 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 8.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:17]([O-])=O)[CH:3]=1>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]([NH2:12])=[N:17][C:4]=2[CH:3]=1
Reactant: N#Cc1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(Cl)ccc2Nc2ccccc21
Temperature: 25 °C
Yield: 144.4 %

Procedure:
Combine 2-(4-chloro-2-nitro-phenylamino)-benzonitrile (1.2 g, 4.4 mmol) in ethanol (40 mL) with a solution of stannous chloride dihydrate (2.9 g, 13.2 mmol) in 12 N hydrochloric acid (13 mL). Stir and reflux for 2 hours, cool to ambient temperature and concentrate. Add water (200 mL), filter and dry to give (890 mg, 72%) of the title compound as a yellow solid: 1H NMR (DMSO-d6) δ 6.84–6.69 (m, 5E), 7.27–7.17 (m, 2H), 8.02 (s, 1H), 8.83 (bs, 1H), 9.36 (bs, 1H); MS (APCI) m/z (rel intensity) 244.3 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([O:71][C:72](=[O:82])[CH2:73][CH2:74][CH2:75][NH:76][CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[CH3:70]>CN(C=O)C>[CH2:69]([O:71][C:72](=[O:82])[CH2:73][CH2:74][CH2:75][N:76]([C:15](=[O:16])[C:14]1[CH:18]=[C:19]([Cl:21])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:13]=1)[CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[CH3:70]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CCOC(=O)CCCNC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.300 g), TBTU (0.482 g) and HOBt (0.150 g) in DMF (5 ml) was added DIPEA (0.260 ml) followed by 4-cyclopentylamino-butyric acid ethyl ester (0.316 g) after 10 min. The reaction mixture was stirred at room temperature for 16 h and then further 4-cyclopentylamino-butyric acid ethyl ester (0.316 g) was added. After 24 h, the reaction mixture was concentrated under reduced pressure to give a viscous gum which was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further water, aqueous saturated sodium bicarbonate solution, water and dried with brine and over sodium sulphate. The organic phase was concentrated under reduced pressure to give crude product as a black gum (0.420 g) which was purified by preparative hplc and the title compound (0.189 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C(O)(=O)C1C=CC=CC=1.N1CCCCC1.Cl>C1(C)C=CC=CC=1>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[C:32](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14](=[CH:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=3)=[CH:26][CH:27]=2)[S:28]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 39 (4.0 g, 11.2 mmol), thiazolidine-2,4-dione (1.31 g, 11.2 mmol), and benzoic acid (1.64 g, 13.4 mmol) in 100 mL toluene was added piperidine (1.66 mL, 16.8 mmol). The mixture was vigorously refluxed with Dean Stark apparatus for 1.5 h under argon then cooled to room temperature. 5% HCl was added to pH 1. The solid was filtered, recrystallized out of toluene, filtered, and washed with hexane before drying under vacuum to a yellow solid (quantitative). 1H NMR (400 MHz, DMSO-d6) δ 12.70 (br s, 1H), 12.59 (br s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.22 (d, J=9.2 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.12 (d, J=9.2 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:13]=[C:14]([Cl:21])[C:15]2[CH:20]=[CH:19][NH:18][C:16]=2[N:17]=1.[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29]Cl)([CH3:25])[CH3:24]>C1COCC1>[Cl:11][C:12]1[N:13]=[C:14]([Cl:21])[C:15]2[CH:20]=[CH:19][N:18]([CH2:29][O:28][CH2:27][CH2:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:16]=2[N:17]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
In a 1000 mL flask, LiHMDS (140 mL, 140 mmol) was diluted in dry THF (100 mL) and cooled to −78° C. The 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 133 mmol) was suspended in THF (200 mL) using gentle warming and sonication. This suspension was added dropwise to the base solution over 30 min. 50 mL more THF was used to dissolve any residue and this suspension was also added dropwise. After complete addition, the mixture was allowed to stir at −78° C. for 30 min. SEM-Cl (25 mL, 140 mmol) was added dropwise to the mixture and stirring was continued at −78° C. for 30 min. Then, the ice bath was allowed to slowly warm to rt overnight. The reaction was quenched by the addition of cold water (150 mL). EtOAc (200 mL) was added and the layers separated. The resulting aqueous layer was then extracted with EtOAc (two×200 mL). The combined organics were washed with brine (two times) and dried over MgSO4, filtered and concentrated. The orange oil was purified via gravity “plug” chromatography eluting with 80% heptanes/20% DCM eluant to afford the title compound (33.4 g, 79% yield) as an orange oil which solidified upon standing. 1H NMR (400 MHz, chloroform-D) δ ppm-0.03 (s, 9H), 0.85-0.99 (m, 2H), 3.50-3.59 (m, 2H), 5.61 (s, 2H), 6.67 (d, J=3.53 Hz, 5H), 7.38 (d, J=3.78 Hz, 1H). m/z (APCI+) for C12H17Cl2N3OSi 318.00/320.05 (M+H)+ for Cl isotopes.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]1[C:5]([N+:24]([O-])=O)=[CH:6][C:7]([N+:21]([O-])=O)=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:9]=1)[CH3:2].C([O-])=O.[NH4+]>O1CCOCC1.CO.[Pd]>[NH2:24][C:5]1[C:4]([N:3]([CH2:27][CH3:28])[CH2:1][CH3:2])=[CH:9][C:8]2[NH:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:21][C:7]=2[CH:6]=1
Reactant: CCN(CC)c1cc(NC(=O)c2ccccc2OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: CCN(CC)c1cc2[nH]c(-c3ccccc3OC)nc2cc1N
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To the solution of 5-(diethylamino)-2,4-dinitro-1-(2-methoxybenzoyl)aminobenzene (388 mg, 1.0 mmol) in 10 mL of 1,4-dioxane and 10 mL of methanol, was added ammonium formate (1.5 g) and 10% Pd/C (200 mg) under nitrogen atmosphere. The reaction mixture was stirred for 30 min. The Pd/C and excess ammonium formate were filtered. Conc. HCl (10 mL) was added to the filtrate. After heating at 75° C. for 18 h, the reaction mixture was basified to pH 8 with saturated K2CO3 solution. The reaction mixture was diluted with 200 mL of ethyl acetate, washed with brine, and dried over anhydrous MgSO4. The reaction mixture was filtered and concentrated in vacuo to afford the crude product (280 mg, 90% yield). The crude product was then purified by column chromatography on silica gel using EtOAc as the eluant to afford the desired product (188 mg, 61% yield) as a brown solid: 1H-NMR (300 MHz, CDCl3) δ 1.01 (t, 6H, J=7.2 Hz), 3.01 (q, 4H, J=7.2 Hz), 4.05 (s, 3H), 6.92 (s, 1H), 7.03 (d, 1H, J=8.1 Hz), 7.11 (t, 1H, J=8.1 Hz), 7.36 (t, 1H, J=6.9), 7.41 (s, 1H), 8.52 (d, 1H, J=7.8 Hz); ESI MS m/z 311.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].[F-].C([NH3+])(C)(C)C>C1COCC1.O>[N+:16]([CH2:19][C:8]1([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of Methyl 1,4-dioxaspiro[4.5]dec-8-ylideneacetate (4 g, 18.8 mmol) in dry THF (20 mL) was treated by nitromethane (1.5 mL, 28.3 mmol) followed by tertbutylammonium fluoride (18.8 mLot a 1M solution in THF, 0.0188 mol). The resulting mixture was stirred at reflux for 18 h under nitrogen. After cooling to RT, the mixture was diluted with water and extracted with MTBE (3×100 mL). Combined organic layers were washed with 10% sodium bicarbonate solution (20 mL), water (100 mL) and brine (50 mL), dried over sodium sulphate filtered and concentrated. Purification by flash chromatography on silica (Pet.Ether:EtOAc) afforded the title compound as a colorless liquid (2.5 g, 49%). 1H NMR (400 MHz, DMSO) δ 4.7 (s, 2H), 3.94 (s, 4H), 3.69 (s, 3H), 2.57 (s, 2H), 1.74 (m, 8H).