Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
1.8 g (60 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 7.5 g (50 mmol) of 4-formylbenzoic acid, dissolved in 100 ml of DMF, are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. A solution of 7.1 ml (60 mmol) of benzyl bromide in 50 ml of DMF is then introduced dropwise and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (50:50). After evaporation of the solvents, 10.9 g (91%) of the expected benzyl ester are collected in the form of a colorless oil.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:20][CH2:21][N:22]([C:1]([Cl:4])=[S:2])[CH2:23][CH2:24]1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCN(C(=S)Cl)CC3)c2cc1OC
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of 3.06 ml (40.1 mmol) of thiophosgene in 100 ml of dichloromethane were slowly added a solution of 10 g (36.5 mmol) of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline obtained by the method described in South African Patent No. 67 06512 (1968) in 100 ml of dichloromethane and 12.4 ml (89.1 mmol) of triethylamine under ice-cooling. The resulting mixture was stirred at the same temperature in an atmosphere of argon for 2 hours. After the solvent was evaporated, the residue was purified by silica gel chromatography to give 6.65 g (52%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100-mL RBF was combined 2-(4-fluorophenylamino)benzoic acid (2.5 g, 11 mmol), HATU (4.9 g, 13 mmol), 4-aminophenol (1.0 g, 9.2 mmol), N-ethyl-N-isopropylpropan-2-amine (3.2 mL, 18 mmol), and DCM (23 mL, 9.2 mmol). The reaction mixture was allowed to stir at RT overnight and was then absorbed onto a loading cartridge and passed through an 80 g silica gel column using hexanes: EtOAc as eluent. Fractions containing pure product were concentrated in vacuo to afford 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide as a brown oil. The oil was triturated with CH2Cl2 and hexanes, and the resulting solid was filtered through a 0.45 μM membrane filter and rinsed with hexanes. 2-(4-fluorophenylamino)-N-(4-hydroxyphenyl)benzamide was isolated as a off-white solid. Calcd for C19H15FN2O2: [M]+=322. Found: [M+H]+=323.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)ethylamine hydrochloride (1.72 g) and sodium hydrogencarbonate (5.00 g) were dissolved in water (25 mL), to which ethyl acetate (25 mL) was added, followed by being stirred in an ice bath. Methacryloyl chloride (1.79 g) was added dropwise thereto. After stirring for 10 minutes, the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The recrystallization was performed by using a mixture solvent of hexane and ethyl acetate. N-[2-(4-Nitrophenyl)ethyl]methacrylamide was obtained as pale yellowish crystals. The yield was 1.25 g (63%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: I.CS[C:4](=[N:19][CH3:20])[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH2:21]([NH:25][C:4]([NH:19][CH3:20])=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Agent: CC(=O)[O-]
Agent: I
Agent: [Pb+2]
Solvent: O
Solvent: CCO
Product: CCCCNC(=Nc1cc(C)ccc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (12.2 g prepared as described in Example 227), n-butylamine (2.4 g) and ethanol (80 ml) was stored at ambient temperature for 4 months. Lead acetate trihydrate (9 g) was then added and the mixture heated under reflux for one hour to yield 1-(n-butyl)-2-(5-methyl-2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 150° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13](CS([O-])(=O)=O)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[N:21]([C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[N+:22]=[N-:23]
Reactant: O=S(=O)([O-])C[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 90 °C

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.686 g, 5.71 mmol) from Step C and sodium azide (0.557 g, 8.56 mmol) were combined in N,N-dimethylacetamide (10 mL). The reaction was heated at 90° C. for 15 hours. The reaction was cooled and diluted with 200 mL of ethyl acetate and then quenched with 30 mL water. The organic layer was removed and washed with 2×20 mL of water, then 20 mL of brine. The solvent was removed in vacuo to give (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole: 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.22 (dd, J=2.9, 5.8, 1H), 3.72-3.61 (m, 1H), 3.54 (s, 2H), 2.76-2.60 (m, 1H), 2.55-2.40 (m, 4H), 2.35 (dd, J=3.5, 9.1, 1H), 2.07-1.86 (m, 2H), 1.72-1.60 (m, 1H), 1.49-1.38 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)cn1
Temperature: 90 °C
Yield: 4.6 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and 2-Aminopyridine-5-boronic acid pinacol ester (MW 220) (243 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichioro 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 14 h 45 min, cooled and diluted with EtOAc (9 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from=% MeOH in DCM to 5% MeOH in DCM) gave a colorless solid (4.40 mg, 5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[C:13]([F:18])[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[F:21])=[C:4]([F:22])[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[C:13]([F:18])[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[F:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(Br)cc2F)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(F)c(N)c(Nc2ccc(Br)cc2F)c1F
Temperature: 70 °C
Yield: 78.6 %

Procedure:
A suspension of (4-bromo-2-fluoro-phenyl)-(2,5-difluoro-3-methoxy-6-nitro-phenyl)-amine (Intermediate 16, 0.850 g, 2.2 mmol) in ethanol (13 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (1.2 g, 6.7 mmol) in water (2.4 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield N2-(4-bromo-2-fluoro-phenyl)-3,6-difluoro-4-methoxy-benzene-1,2-diamine as a brown solid (600 mg). 1H-NMR (400 MHz, CDCl3): δ 3.61 (2H, bs), 3.82 (3H, s), 5.40 (1H, bs), 6.37 (1H, t), 6.68-6.73 (1H, m), 7.06 (1H, d, J=8.4), 7.24 (1H, d, J=14).
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=[O:4].[C-:13]#[N:14].[K+].C(O)(=O)C>CO>[NH2:14][CH2:13][C@H:3]([OH:4])[C@@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:1]
Reactant: [C-]#N
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 5.25 g (30.4 mmol) of tert-butyl (1S)-1-methyl-2-oxoethylcarbamate in 30 mL of methanol at 0° C. was added 2.18 g (33.4 mmol) of potassium cyanide, followed by 1.74 mL (33.4 mmol) of acetic acid. The reaction mixture was warmed to room temperature, left stirring for 16 h, and then filtered and concentrated under vacuum. The residue was dissolved in 80 mL of acetic acid, and 0.8 g of platinum oxide on carbon was added. The reaction mixture was then stirred under 40 psi of hydrogen for 4 h. The catalyst was filtered off over celite, and the filtrate was washed with methanol and concentrated to afford 3.06 g (49%) of tert-butyl (1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl (1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 6.74, 6.59 (d, J=8 Hz, 1H), 3.61–3.38 (m, 3H), 2.80 (m, 1H), 2.51 (m, 2H), 1.45 (br s, 1H), 1.38 (s, 9H), 0.97 (m, 3H). GC-MS m/z 205 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:34][CH2:33]1.C(I)C>CN(C)C=O>[CH2:33]([O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2)[CH3:34]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To an ice-cooled and stirred solution of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g) and potassium carbonate (0.50 g) in N,N-dimethylformamide (10 mL)-tetrahydrofuran (30 mL) was added ethyl iodide (0.28 mL), and the mixture was stirred at room temperature for 18 h and then at 55° C. for 15 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=25:75 to 40:60, volume ratio) to give the title compound (0.65 g, 50%) as light yellow crystals. MS 391 (MH+).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2]2.C(O)(=O)C.[CH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH2:15]>CO>[N:19]1[CH:20]=[CH:21][C:16]([CH2:14][CH2:15][N:4]2[CH:3]=[CH:2][N:1]3[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:5]2)=[CH:17][CH:18]=1
Reactant: C=Cc1ccncc1
Reactant: C1CC2CNCCN2C1
Solvent: CO
Solvent: CC(=O)O
Product: C1=Cn2cccc2CN1CCc1ccncc1

Procedure:
A solution of 12 g (0.095 mole) 1,4-diazabicyclo[4.3.0]-nonane, 10 ml of acetic acid and 12.5 ml of 4-vinylpyridine in 225 ml methanol was heated at reflux for 20 hours. The solvent was removed under vacuum and the residue distilled to yield 5.1 g of 2(4-pyridylethyl)pyrrolo[1,2-a]pyrazine; b.p. 126°-130/0.01 mm.
Reaction SMILES: C([O:3][C@@H:4]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:6]([CH2:7][C:8](=[O:35])[C@@H:9]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:25])[CH2:15][CH2:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:5]1)=O.CC(C)=O.[OH-].[Na+]>O>[OH:3][C@@H:4]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:6]([CH2:7][C:8](=[O:35])[C@@H:9]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:25])[CH2:15][CH2:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:5]1
Reactant: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
To 10 grams of 2-(3α-formyloxy-7-keto-5β-cholan-24-amido)-2-methyl-1-propanol in 300 ml. of acetone was added dropwise, 200 ml. of 0.2N sodium hydroxide over a period of 30 minutes and the mixture was then permitted to stand for 1 hour. One liter of water was added to yield white crystals which were then filtered washed with water, dried and recrystallized from chloroform-acetone to obtain 2-(3α-hydroxy-7-keto-5β-cholan-24-amido)-2-methyl-1-propanol.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:5]1[CH2:6][C@@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([O:9][CH3:10])=[O:8])=[O:24]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1Br
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
Into a flame-dried 100 ml three-necked round-bottomed flask containing 30 ml of distilled THF was placed 3.00 g (16.575 mmol) of (cis)-4-hydroxy-L-proline, methyl ester; the vessel was immersed in an ice/water bath and the suspension was allowed to stir under argon for 5 minutes. At this time, 6.35 ml (36.465 mmol) of diisopropylethylamine was added slowly via syringe; the mixture was allowed to stir for 10 minutes, whereupon 3.64 g (16.576 mmol) of 2-bromobenzoyl chloride was added dropwise via syringe over the course of 10 minutes. The mixture was allowed to stir at 0° for 2 hours then gradually brought to room temperature overnight. The mixture was concentrated under vacuum to a minimal volume, transferred to a separatory funnel, and diluted with 100 ml of ethyl acetate, then washed with 1N HCl (2×30 ml), saturated sodium bicarbonate (2×30 ml), and brine (30 ml). The organic solution was dried over sodium sulfate, filtered, and concentrated under vacuum. Recrystallization from hot ethyl acetate yielded 3.034 g (55.6%) of the title compound, m.p. 145.5°-146.8° C.; a second recrystallization of the mother liquor yielded 1.726 g to bring the net yield to 4.760 g (87.3%).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:8])[CH2:6][CH3:7].Cl[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([C:15]([NH:17][C:18]2[S:19][C:20]3[C:26]([CH:27]4[CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28]4)=[CH:25][CH:24]=[C:23]([O:34][CH3:35])[C:21]=3[N:22]=2)=[O:16])=[CH:13][CH:12]=1>O>[O:32]1[CH2:33][CH:27]([C:26]2[C:20]3[S:19][C:18]([NH:17][C:15](=[O:16])[C:14]4[CH:13]=[CH:12][C:11]([CH2:10][N:4]([CH3:3])[C:5](=[O:8])[CH2:6][CH3:7])=[CH:37][CH:36]=4)=[N:22][C:21]=3[C:23]([O:34][CH3:35])=[CH:24][CH:25]=2)[CH2:28][O:29][CH2:30][CH2:31]1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CCC(=O)NC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)cc1
Temperature: 55 °C
Yield: 4 %

Procedure:
Sodium hydride (4.8 mg, 60% disp. in mineral oil, 0.2 mmol) was added to N-methylpropionamide (1 ml, 11 mmol), followed by 4-chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide (50 mg, 1.2 mmol) and the reaction mixture was heated to 55° C. for 3 hrs. After cooling, the mixture was diluted with water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined organic phases were dried with magnesium sulfate, filtered and evaporated. Final purification with preparative HPLC and final dry-freezing afforded the title compound as white solid (23 mg, 42% yield). MS: m/e=484(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:10].[H-].[Na+].[CH3:39][Si:40]([CH3:47])([CH3:46])[CH2:41][CH2:42][O:43][CH2:44]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25]2)[CH:5]=[CH:6][C:7]=1[N:8]([CH2:44][O:43][CH2:42][CH2:41][Si:40]([CH3:47])([CH3:46])[CH3:39])[C:9]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)=[O:10]
Reactant: COc1ccc(-c2ccc(C(=O)Nc3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)N(COCC[Si](C)(C)C)c3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A solution of (S)-tert-butyl 1-{3-bromo-4-[5-(4-methoxyphenyl)thiophene-2-carboxamido]phenyl}pyrrolidin-3-ylcarbamate (400 mg, 0.69 mmol) in THF (20 mL) was cooled to 0° C. and sodium hydride (60 wt %, 140 mg, 3.5 mmol) was added. The reaction was warmed to room temperature followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (370 mL, 2.1 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (400 mg, 87%): ESI MS m/z 703 [C33H44BrN3O5SSi+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[N:23]1([CH2:22][CH2:21][NH:20][C:1]([C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NCCN1CCOCC1
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(NCCN1CCOCC1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:13][C:3]1[C:2]([CH3:1])=[CH:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: Cc1cn(-c2ccccc2)nc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cn(-c2ccccc2)nc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 202 %

Procedure:
To a solution of (4-methyl-1-phenyl-1H-pyrazol-3-yl)methanol (158 mg, 0.84 mmol) and triphenylphosphine polymer bound (422 mg, 1.26 mmol) in dichloromethane (4.5 mL) was added carbon tetrabromide (416 mg, 1.26 mmol) at 0-5° C. The ice bath was removed after 15 min and the mixture was stirred at RT for 2 h. The mixture was filtered, washed with dichloromethane and the solvent was evaporated to give 426 mg crude material. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow oil (115 mg, 458 μmol, 38.3%).