Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[C:10]([O:11][CH3:12])=[C:2]([Cl:1])[C:3]([OH:13])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(O)c1Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Br)cc(C(=O)O)c(O)c1Cl
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 3-chloro-2-hydroxy-4-methoxybenzoic acid (11.1 g) in acetic acid (275 mL) was added bromine (8.79 g) at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture was added water, and the precipitate was collected by filtration. The precipitate was washed with water, and dissolved in ethyl acetate, and the solution was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.4 g).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C(CC(O)=O)C.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])[C:30](=[N:37][OH:38])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13].[N-]=C=O>>[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])[C:30](=[N:37][O:38][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: CCN=C=O
Agent: [N-]=C=O
Solvent: CCCC(=O)O
Product: CCNC(=O)ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To ethyl isocyanate (5 ml.) was added 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid ethyl acetate solvate (syn-isomer) (0.9 g.) and the mixture stirred for one hour at room temperature. Two further portions of the isocyanate (5 ml.) were added, over a period of two hours. The mixture was then allowed to stand for one hour, and poured into petroleum (b.p. 40°-60°; 250 ml.) and the resulting precipitate collected, washed thoroughly with petroleum and dried. The solid was dissolved in ethyl acetate and extracted into sodium bicarbonate solution; the bicarbonate solution was then washed with ethyl acetate, acidified (2 N-hydrochloric acid) and extracted with ethyl acetate. The combined extracts were dried and concentrated, and the concentrate (ca. 5 ml.) added dropwise to petroleum spirit with vigorous stirring. The precipitate formed was filtered and dried, giving the title acid (0.4 g.; 47%), [α]D +50° (c 0.85, DMSO), λmax. (pH 6 buffer) 257.5 nm (ε 21,200), νmax. (Nujol) 1782 (β-lactam), 1675 and 1520 cm.-1 (CONH), τ (DMSO-d6) values include 0.04 (doublet J 8 Hz; NH), 2.0-2.6 (multiplet; aromatic protons), 6.7-7.1 (multiplet; NHCH2CH3) and 8.89 (triplet, J 9 Hz; CH2CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOc1nc(Cl)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
12 gm (0.037 mol) of 6-ethoxy-2-chloro-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine were stirred together with 22 gm (0.28 mol) of piperazine in ethanol at 40°C for 2 hours. Then, the reaction mixture was poured into water, and the precipitate formed thereby was suction-filtered off and recrystallized from ethanol. Yield: 13 gm (93.8% of theory); m.p. 223°-224°C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 440 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[Br:29][CH2:30][C:31](O)=[O:32]>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC.CCOC(C)=O>[Br:29][CH2:30][C:31]([CH2:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1])=[O:32]
Reactant: O=C(O)CBr
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CC(=O)CBr
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
A mixture of 100 mg of cholesterol and 40 mg of bromoacetic acid (1.1 eq) was dissolved in 10 mL of anhydrous dichloromethane. Then 44 μl (1.1 eq) of DIPC(N,N-diisopropylcarbodiimide) and 1.5 mg (0.05 eq) of DMAP (4-dimethylaminopyridine) were added. The solution was left stirring at room temperature for 48 h and analyzed by TLC using a mixture of n-hexane/EtOAc 10/1 as solvent systems. The solvent was evaporated and the reaction product was purified by silica gel flash chromatography in n-hexane/dichloromethane 1/1. The fractions containing the product were pooled, evaporated and then lyophilized in water/acetonitrile 20/80. The purified product was analyzed by NMR. Yield: 73%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:28])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2Br)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=S)Nc2ccccc2Br)cc1

Procedure:
To a solution of EXAMPLE 1A (15 g) in toluene (55 mL) was added Lawesson's reagent (11.49 g) and the mixture heated at reflux for 4 hours. The mixture was cooled and concentrated and the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and brine. The organic layers were concentrated and the crude material was triturated with ethyl acetate and filtered to afford title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19](COCC[Si](C)(C)C)[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:29])([F:28])[F:30])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:40])[C:18](=[O:39])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:29])([F:28])[F:30])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:40])[C:18](=[O:39])[NH:19][N:20]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Product: C[C@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 21 %
Yield: 22 %

Procedure:
To a solution of 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (1.6 g, 2.73 mmol) in THF (5 mL) was added a solution of TBAF (1 M in THF, 4.1 mL, 4.1 mmol). The reaction mixture was heated at reflux for 3 days then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by chiral SFC separation (Table 2, Method 2) to give 3-(4(S)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 6), Rt=8.78 min., 0.280 g, 22%) and 3-(4(R)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 6), Rt=10.53 min., 0.260 g, 21%). 1H NMR (CDCl3, 400 MHz): δ 8.18 (s, 1H), 7.18 (s 1H), 5.91 (s, 1H), 4.68 (q, J=6.8 Hz, 1H), 4.61 (d, J=12.8 Hz, 1H), 4.52 (m, 1H), 4.51 (d, J=12.8 Hz, 1H), 4.36 (m, 2H), 4.22 (m, 1H), 3.80 (m, 2H), 1.55 (d, J=6.8 Hz, 3H), 1.49 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:26][C@@H:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2ccc(F)cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1ccc(-c2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
4′-Fluoro[1,1′-biphenyl]-3-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[C:3]=1[CH:4]=O>CO.[C].[Pd]>[CH3:4][C:3]1[C:6]([CH3:12])=[CH:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:2]=1[OH:1]
Reactant: Cc1cc(C)c(C=O)c(O)c1C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C)c(O)c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 12.1 %

Procedure:
2-Hydroxy-3,4,6-trimethylbenzaldehyde (6.58 g, 40.1 mmol) was dissolved in methanol (120 mL), 10% palladium-carbon (50% water-containing product, 1.0 g) was added under hydrogen atmosphere (balloon pressure), and the mixture was stirred at room temperature for 22 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The precipitated crystals were recrystallized from methanol to give the title compound (0.73 g, yield 12%) as colorless crystals. The mother solution was concentrated under reduced pressure to give second crop (5.10 g, yield 85%). MS m/z 151 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](C1C=C(B2OC(C)(C)C(C)(C)O2)C=C(C(NC)=O)C=1)=O.[Br:24][C:25]1[CH:26]=[C:27]([C:35]([O:37]C)=O)[CH:28]=[C:29]([CH:34]=1)[C:30](OC)=[O:31].C[NH2:40]>C(O)C>[CH3:1][N:2]([CH3:3])[C:35](=[O:37])[C:27]1[CH:26]=[C:25]([Br:24])[CH:34]=[C:29]([C:30]([NH2:40])=[O:31])[CH:28]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)NC)c1
Reactant: CN
Solvent: CCO
Product: CN(C)C(=O)c1cc(Br)cc(C(N)=O)c1

Procedure:
Mannosides were synthesized by traditional Lewis acid mediated glycosylation of mannose penta-acetate by reaction with 2-substituted 4-bromophenols using BF3 etherate (Scheme 1). Suzuki cross-coupling with commercially available 3-substituted phenyl boronic acid derivatives gave protected ortho-substituted 4′-biphenyl mannosides in excellent yields and subsequent deprotection with NaOMe gave mannosides 4-5. 6 was prepared following the procedure previously described. Synthesis of di-amides 7-8 followed a similar procedure but required the synthesis of 3,5-di-(N-methyl aminocarbonyl)phenyl boronic acid pinacol ester 9. Shown in Scheme 1, amidation of dimethyl 5-bromoisophthalate by reaction of methylamine in ethanol proceeded in quantitative yield to give N,N-dimethyl 5-bromoisophthalamide. Installation of the boronate ester was accomplished by Pd-mediated coupling with bis(pinacolato)diboron to give 9. Suzuki coupling and deprotection as before yielded compounds 7-8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:26][O:25][C:23](=[O:24])[C:22]([C:21]1[N:18]=[C:9]([C:10]2[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:20]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)C(C)(C)C(=O)CBr
Reactant: N=C(Nc1ccc(Br)cc1)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C(C)(C)c1cn(-c2ccc(Br)cc2)c(-c2c(Cl)cccc2Cl)n1
Temperature: 170 °C
Yield: 57 %

Procedure:
A mixture of N-(4-bromophenyl)-2,6-dichlorobenzamidine (1.03 g, 3.0 mmol), methyl 4-bromo-2,2-dimethylacetoacetate (1.78 g, 8.0 mmol) and NaHCO3 (0.76 g, 9.0 mmol) in isopropanol (12 mL) was heated in a microwave unit (Biotage Initiator™) at 170° C. for 25 min. The resulting mixture was decanted and the solids rinsed with EtOAc. The combined filtrates were concentrated and purified by chromatography (silica, EtOAc/Hex, 15:85 to 50:50) to give the title compound (0.80 g, 57%) as a pale yellow solid. 1H-NMR (DCM-d2): δ 7.44 (d, 2H), 7.27-7.34 (m, 3H), 7.09 (m, 2H), 3.67 (s, 3H), 1.61 (s, 61-1); MS (ES): 467, 469, 471 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([NH:21][CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:5][CH:4]=1.ClC(Cl)C.[N:29]1([C:35]([N:37]2[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([N:21]([CH2:43][CH:40]3[CH2:41][CH2:42][N:37]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[CH2:38][CH2:39]3)[CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: O=CC1CCN(C(=O)N2CCOCC2)CC1
Reactant: CCCN[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
(R)-N-{2-[3-(4-Methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-propylamine (0.32 g), dichloroethane (20 ml) and 1-(morpholine-4-carbonyl)piperidine-4-carboxaldehyde (0.32 g) and were stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (0.5 g) was added, and the mixture stirred at room temperature for about 72 hours. The mixture was diluted with diethyl ether (50 ml) and 10% sodium hydroxide solution (20 ml). The organic layer was dried with sodium sulfate, filtered, and the solvent evaporated in vacuo. The residue was chromatographed, eluting with methanol/dichloromethane to give (R)-N-{2-[3-(4-methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-N-propyl-[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]amine, (0.42 g), [α]D25−42° (c 1.0 CH3OH); M+H 537.
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13](OC(=O)C)[O:14]C(=O)C)=[C:7]([N+:22]([O-:24])=[O:23])[C:6]=1[O:25][CH3:26])(=O)C>Cl>[CH3:26][O:25][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[OH:4])[CH:13]=[O:14]
Reactant: COc1cc(C(OC(C)=O)OC(C)=O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Agent: Cl
Product: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1O
Yield: 97.9 %

Procedure:
A suspension of 43 g (0.116 mole) of 4-acetoxy-1-diacetoxymethyl - 3,5-dimethoxy-2-nitrobenzene in 500 cm3 of 2N hydrochloric acid is heated under reflux for 2 hours. The reaction mixture is left to return to ambient temperature, then the precipitate formed is filtered off. After washing with water and drying under vacuum, 25.8 g of the desired product is obtained in the form of a slightly yellow solid (yield =98%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=O)[C:27](O)=[O:28])[CH:20]=1>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:27](=[O:28])[C:26]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[N:18][C:17]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncccc2N)c1
Reactant: O=C(O)C(=O)Cc1cccnc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 67.8 %

Procedure:
A mixture of 2-(3-acetamidophenylamino)-3-aminopyridine (1.0 g) and 3-(3-pyridyl)pyruvic acid (0.82 g) in ethanol (50 ml) was stirred under reflux for 6 hours. After evaporation of the solvent, crude residue was chromatographed on silica gel and crystallized from ethyl acetate to give 4-(3-acetamidophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.04 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cc1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(4-methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid 161 and amine 14.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21](O)=[O:22])[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:21]([C:19]2[NH:18][C:15]3=[N:16][CH:17]=[C:12]([O:11][CH:8]4[CH2:9][CH2:10][N:5]([CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]4)[CH:13]=[C:14]3[CH:20]=2)=[O:22])=[CH:49][CH:48]=1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)NCc4ccc(F)cc4)cc3c2)CC1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from 5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 4-fluorobenzylamine and N,N-diisopropylethylamine (7 eq.) in DMF to give the desired product as a light yellow solid (37%).
Reaction SMILES: F[S:2]([C:5]([C:8]([C:11]([C:14]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[OH-:25].[Li+:26].[OH-].C(=O)=O>CO>[S:2]([C:5]([C:8]([C:11]([C:14]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([O:25][Li:26])(=[O:4])=[O:3]
Reactant: [Li+]
Reactant: [OH-]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OCc1ccccc1
Agent: O=C=O
Solvent: CO
Product: [Li]OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OCc1ccccc1
Temperature: 75 °C

Procedure:
FSO2(CF2)4OCH2C6H5 was treated with excess aqueous lithium hydroxide as described in Preparation of Precursor 3 except that the solution was heated at 75° C. for eighteen hours. After neutralization of the excess hydroxide with solid carbon dioxide, it was noted that a lower fluorochemical-containing phase was still present. Additional lithium hydroxide was added as well as about 50 mL of methanol and the reaction mixture heated to 84° C. for an additional eighteen hours. This solution was then neutralized in the usual manner and LiO3S(CF2)4OCH2C6H5 was isolated after alcohol extraction (9.4 g).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]=NC2C=CC=CC=2OC)=[CH:13][CH:12]=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1.C[Mg+].[Br-].[CH3:34]COCC.[CH2:39]1[CH2:43]OC[CH2:40]1>>[C:10]1([CH:9]([C:14]2[CH:13]=[CH:12][CH:11]=[CH:34][CH:15]=2)[OH:8])[C:25]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:43]=[CH:39][CH:40]=1
Reactant: C1CCOC1
Reactant: COc1ccccc1N=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Product: OC(c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A solution of crude 17 (˜5 mmol, 1.0 equiv) in THF (25 mL) was cooled in an ice-bath and 3M MeMgBr in Et2O (4.0 mL, 12.0 mmol, 2.4 equiv) was added dropwise via syringe and <5° C. The mixture was stirred at <5° C. for 10 min then allowed to warm to room temperature and stirred 1 hr. The mixture was recooled to ˜8° C. and quenched with saturated NH4Cl solution (5 mL). The mixture was diluted with H2O (20 mL) and extracted with 1:1 EtOAc/heptanes (100 mL). The organic phase was washed with brine (25 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving a yellow oil. The crude product was dissolved in few mL of dichloromethane/heptanes, absorbed onto silica gel and dry-loaded on a column of silica gel (30 g) packed in heptanes. The column was eluted with heptanes (150 mL), 2% EtOAc/heptanes (250 mL) and 3% EtOAc/heptanes (250 mL). Product fractions were concentrated under reduced pressure to give 1.90 g (93%) of 7 as a nearly colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=[O:9])[N:6]=1.[CH3:14][N:15]([CH3:18])[CH:16]=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].O1CCC[CH2:27]1>CO>[CH3:14][N:15]([CH:18]=[N:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([O:10][CH3:27])=[O:9])[N:6]=1)[CH3:16]
Reactant: CN(C)C=O
Reactant: C1CCOC1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CO/N=C(\C(=O)OC)c1csc(N=CN(C)C)n1
Temperature: 5 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (0.5 g, 2.5 mmol) was dissolved in 20 ml of tetrahydrofuran. Subsequent to the addition of 0.72 g (9.9 mmol) of dimethylformamide, the resulting solution was cooled to 5° C. The solution was added with 1.52 g (9.9 mmol) of phosphorus oxychloride and the resulting mixture was stirred for 3 hours. Methanol (20 ml) was added to the reaction mixture, followed by stirring for 10 minutes. A 2N aqueous solution of sodium hydroxide was added to the reaction mixture to adjust its pH to 7. The reaction mixture so obtained was extracted three times with 100 ml portions of chloroform. The organic phases were combined and then dried. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 0.63 g of the title compound was obtained (yield: 94%).