Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CN1CCCC1=O.O>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCc1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) in N-methylpyrrolidone (10 ml) was treated with 4-fluorobenzylamine (0.60 ml). The mixture was stirred at room temp for 18 h and was then diluted with water (50 ml). This gave the title compound as a colourless solid which was collected by filtration and dried (0.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[C:22]([F:30])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:31])[CH:3]=1.B(Cl)(Cl)Cl.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:30])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OC(C)C)c(F)c1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5-[3-(4-Chloro-2-methyl-phenyl)-3-(3-fluoro-4-isopropoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 323, step 4, 1.969 g) in dichloromethane (32.5 mL) was cooled to −10° C. At this temperature boron trichloride solution (1 M in dichloromethane, 13.4 mL) was slowly added. The reaction mixture was stirred at −10° C. for 1 h. The crude reaction mixture was poured into water/sat. sodium hydrogencarbonate-solution, extracted 3× with ethyl acetate, the organic layers were washed 2× with water, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a light yellow solid, MS (ESI−): m/z=397.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under N2 in a 250 mL round-bottomed flask fitted with a reflux condenser and magnetic stirrer, 3,4-dichlorophenol (2.9 g, 17.8 mmol) was added to a suspension of K2CO3 (7.0 g, 51 mmol) in 70 mL of anhydrous DMF. After stirring the mixture for 15 min., 2-chloronicotinaldehyde (2.4 g, 17 mmol prepared according to the method in J. Heterocycl. Chem. 1995, 32, 1595) was added and the mixture was heated to 90–100° C. for 5 h. After allowing the reaction to cool to room temperature overnight, the mixture was diluted with water and extracted three times with EtOAc. The aqueous layer was then extracted with additional EtOAc and the organic layers were combined, washed with water and brine and dried over Na2SO4. Removal of the solvent in vacuo gave a brown solid which was further dried under vacuum overnight and then recrystallized from EtOAc to give the title product as tan crystals, 1.6 g; m.p. 97–99° C. A second crop of tan crystals weighing 0.716 g was later obtained, and concentration of the filtrate provided an additional 2.65 g of nearly pure title product; δH (CDCl3, 400 MHz) 7.08 (1H, dd), 7.17 (1H, m), 7.43 (1H, d), 7.49 (1H, d), 8.25 (1H, dd), 8.33 (1H, dd), 10.50 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:5]2=[O:30].[H-].[Na+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[NH:8][CH2:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:24])[CH3:25])[C:5]2=[O:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Br)c3ccccc32)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1N1CNc2c(cc(Br)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of crude 1,5-anhydro-3-(6-bromo-4-oxobenzo[h]quinazolin-3(4H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol (1.01 g, 2.06 mmol) in DMF (17 mL) was cooled at 0° C. Sodium hydride (95%, 62 mg, 2.58 mmol) was added and the resulting yellow mix was stirred for 5 minutes. Iodomethane (0.27 mL, 4.32 mmol) was added and the reaction was stored in the freezer overnight. LCMS showed the reaction was incomplete. It was put back in an ice bath and additional sodium hydride (50 mg) was added. After 20 minutes, the completed reaction was quenched with ammonium chloride and allowed to warm to room temperature. The reaction was diluted with water and extracted 2× with CH2Cl2. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried. The residue was purified via silica gel chromatography, eluting with 10-55% ethyl acetate in hexanes to provide 1,5-anhydro-3-(6-bromo-4-oxo-1,4-dihydrobenzo[h]quinazolin-3(2H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol that gave a mass ion (ES+) of 506.9 for [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([NH:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31](=[O:35])[NH:32]2)=[CH:28][CH:27]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:30]1[C:29]2[C:33](=[CH:34][C:26]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:27][CH:28]=2)[NH:32][C:31]1=[O:35])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(NC(=O)c3ccccc3)cc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-benzamido-2-oxindole to give 0.4 g of N-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzamide as a yellow-orange solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:9]=1)(=O)=O.[SH:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][S:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Tert-butyl (4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)acetate (5.454 g, 17.347 mmol) was dissolved in acetonitrile (100 ml), methyl 2-mercaptobenzoate (3.502 g, 20.816 mmol) and dipotassium carbonate (4.795 g, 34.694 mmol) was added. The solution was stirred for 10 hours at 60° C. EtOAc (40 ml) was added and the organic phase was washed with two portions of Brine (2×40 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 6.931 g crude of methyl 2-({2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethyl}thio)benzoate. The crude was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN1Cc2cccc(O)c2C1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CN1Cc2cccc(Oc3nc(Cl)ncc3Cl)c2C1=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2,4,5-trichloropyrimidine (0.20 g) and 7-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one are dissolved in DCM (10 mL), cooled to 0° C. and combined with caesium carbonate (0.75 g). The cooling bath is removed and the mixture is stirred for 16 h. For working up the mixture is combined with 10% NaCl solution (100 mL) and extracted three times with 75 mL ethyl acetate. The combined organic phases are dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8]C(=O)OC(C)(C)C)[O:5][CH:6]=1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[O:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)co1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl [(4-bromo-2-furyl)methyl]carbamate (153 g, 55.4 mmol) in dichloromethane (86 mL) at 0° C. was treated with trifluoroacetic acid (43 mL) over 15 minutes. The reaction mixture warmed to room temperature over 30 minutes. The solvent was removed in vacuo and chased with toluene (3×50 mL). The product was lyophilized for 18 hours to give the desired product as a brown solid (13.0 g, 81%). LCMS calculated for C5H4BrO (M−NH2)+: m/z=158.9, 160.9. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (br s, 3H), 8.01 (s, 1H), 6.70 (s, 1H), 4.08 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:13])[C:7]1=[O:25].[CH3:30]O.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:30][O:18][C:17](=[O:19])[CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:25])[N:6]([CH2:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1

Procedure:
(R)-3-(1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-3-(thiophen-2-yl)propanoic acid (0.631 g, 0.00151 mol;) was dissolved in Methanol (10 mL, 0.2 mol;) and cooled to 0 C. Thionyl chloride (600 uL, 0.008 mol;) was then added and the reaction was allowed to warm up o/n. LC-MS showed the formation of product at 1.63 432.97. The reaction was diluted with methylene chloride then washed 1× with sodium bicarbonate and 1× with brine before drying and concentration. The reaction was then concentrated and dissolved in methylene chloride for purification by combiflash using a 0-100 hexanes/ethyl acetate gradient. ES (+) MS m/e=432.97
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: c1ccc(COc2ccccc2OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
In analogy to example 20.a., 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-benzyloxyphenol to give 4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole as a yellow viscous oil. MS (ISP): 523.5 ([M+H]+)
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=1[CH2:12][O:13][C:14]([O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH2:21]O)=[CH:19][C:18]=1[CH3:26])=[O:15])([O-:9])=[O:8].[Cl:31]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N+:7]([C:10]1[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=1[CH2:12][O:13][C:14]([O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH2:21][Cl:31])=[CH:19][C:18]=1[CH3:26])=[O:15])([O-:9])=[O:8]
Reactant: Cc1cc(CO)cc(C)c1OC(=O)OCc1ccccc1[N+](=O)[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(CCl)cc(C)c1OC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 89.1 %

Procedure:
Pyridine (34 mL, 0.42 mmol) was added to a stirring mixture of 8h (56 mg, 0.17 mmol) and triphosgene (60 mg, 0.20 mmol) in a mixture of CDCl3 (1 mL) and CH2Cl2 (2.5 mL) at r.t. After 45 minutes, the reaction mixture was filtered through a pad of silica gel (5 g, 3 cm) washing with CH2Cl2 (20 mL) and concentrated in vacuo to yield pure 9h (53 mg, 90%) as a clear oil which became an off-white solid on addition of hexane: 1H NMR (270 MHz, CDCl3) d 2.20 (s, 6H), 4.50 (s, 2H), 5.70 (s, 2H), 7.09 (s, 2H), 7.50-7.56 (m, 1H), 7.69-7.72 (m, 2H), 8.16 (d, J=7.9 Hz, LH); 13C NMR (68 MHz, CDCl3) d 16.1, 64.7, 66.9, 125.4, 127.5, 128.8, 129.3, 130.3, 131.6, 134.1, 138.9, 147.3, 147.69, 152.7.
Reaction SMILES: C(N(CC)CC)C.[N-:8]=[N+:9]=[N-:10].[Na+].[N+]([C:15]1[CH:34]=[CH:33][CH:32]=[C:17]2[C:18]([N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O>CS(C)=O>[N:8]([C:32]1[CH:33]=[CH:34][CH:15]=[C:16]2[C:21]([N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:18](=[O:19])[C:17]=12)=[O:22])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Temperature: 50 °C
Yield: 80.1 %

Procedure:
1.4 ml (0.01 mol) of triethylamine, followed by 0.72 g (0.011 mol) of sodium azide, are added to a mixture of 3.12 g (0.01 mol) of 4-(3-nitrophthalimidyl)-benzoic acid and 20 ml of dimethylsulphoxide. The reaction mixture is heated for 6 hours at 50° C. and is then evaporated in vacuo at 80° C.; the residue is stirred with 70 ml of water and the resulting solution is then brought to pH 1 with hydrochloric acid. The product which has precipitated is filtered off with suction, washed with 5 ml of methanol and dried for 24 hours in a drying cabinet at 80° C./100 mm Hg. 2.47 g (80% of theory) of 4-(3-azidophthalimidyl)-benzoic acid are obtained; melting point 300° C. (with decomposition). IR spectrum (KBr): 1790 and 1740 cm-1 (CO--N--CO); 2150 cm-1 (N3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([O-])=[O:12].[K+]>>[CH2:16]([O:15][C:9](=[O:14])[CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:12])[CH3:17]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [K+]
Product: CCOC(=O)CC(=O)Nc1cccc(Cl)c1

Procedure:
In a manner similar to that described in Referential Example 370, 3-chloroaniline was condensed with potassium ethyl malonate, whereby the title compound was obtained.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][CH:7]1[C:12](=[O:13])[NH:11][C:10](=[S:14])[NH:9][C:8]1=[O:15].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)C>O>[OH:15][C:8]1[C:7]([CH3:6])=[C:12]([OH:13])[N:11]=[C:10]([S:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=1
Reactant: CC1C(=O)NC(=S)NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CSc1nc(O)c(C)c(O)n1
Yield: 54.3 %

Procedure:
To a solution of 4.0 g (0.0475 mole) of sodium bicarbonate in 40 ml of water was added with stirring 7.5 g (0.0475 mole) of 5-methyl-2-thiobarbituric acid. Ethyl bromoacetate (7.9 g, 0.0475 mole) was then added and 40 ml of ethanol to make a clear solution. After one-half hour a precipitate was formed. Stirring was continued for one-half hour at room temperature. The precipitate was collected and recrystallized from ethanol to give 6.3 g of (4,6-dihydroxy-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester mp. 211°-214°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:29])[O:27][CH3:28])[CH:18]=[CH:19][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]([CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:27][CH3:28])=[O:29])[C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: COC(=O)NCCCNc1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)NCCCN(C(=O)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)acetic acid in CH2Cl2 at 0° C. under argon atmosphere was added DMAP, methyl 3-(3-chlorophenylamino)propylcarbamate and DCC. The reaction mixture was allowed to stir at room temperature for 24 h. The resulting suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was subjected to silica gel chromatography to give tert-butyl 2-((3-chlorophenyl)(3-(methoxycarbonylamino)propyl)amino)-2-oxoethyl(methyl)carbamate. 1H NMR δ 0.7-0.9 (m, 4H), 1.0-1.15 (m, 1H), 1.3 (s, 3H), 1.4 (s, 9H), 1.65 (m, 2H), 2.85 (m, 3H), 3.7 (m, 4H), 3.75 (m, 2H), 5.65 (m, 1H), 7.0-7.2 (m, 1H), 7.25 (m, 2H), 7.4 (m, 2H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[O:8][C:9]([CH3:26])=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]=1)=[O:6]>O1CCCC1.CO>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[CH:11]=[C:7]([C:5]([OH:6])=[O:4])[O:8][C:9]=2[CH3:26])=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
1M Aqueous lithium hydroxide (18 mL) was added to solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (17) (1 g) in tetrahydrofuran/methanol (2:1 by volume, 100 mL) and the mixture stirred at room temperature for 5 h. The solvent was removed in vacuo, the residue dissolved in water (20 mL) and the solution acidified to pH6 with aqueous dilute hydrochloric acid. The mixture was evaporated to dryness and the residue was purified by HPLC to afford compound 18 as a white solid (210 mg). LC/MS System B: Rt=4.80 mins, m/z=307 ((M−1) for C19H16O4).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17]([OH:19])=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:48]1[CH2:49][CH2:50][N:45]([CH2:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[CH:30][CH:31]=[C:32]([CH:51]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:46][CH2:47]1)(=[O:19])[CH3:16]
Reactant: Clc1cnc2nc1Nc1ccc(CN3CCNCC3)c(c1)CCc1cccc(c1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCN(Cc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-12-(piperazin-1-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 52% yield. LCMS for C25H28ClN6O (M+H)+: m/z=463.2.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][OH:5].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Si:25]([O:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:2]([F:14])([F:15])[F:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC(CO)C(F)(F)F
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(F)(F)F
Yield: 94 %

Procedure:
To a stirred solution of 340 (240 mg, 1.047 mmol) in DCM (3 mL) at 0° C. under nitrogen was added solid imidazole (71.29 mg, 1.047 mmol) followed by tert-butylchlorodiphenylsilane (272.3 μL, 1.047 mmol) neat by syringe. After 4 h the reaction was diluted to 30 mL with DCM and was washed 2N HCl (2×30 mL) and satd. aq. NaHCO3 (2×30 mL). The organic phase was isolated, dried (MgSO4), filtered and concentrated to afford 460 mg (94%) of tert-butyl 3-(tert-butyldiphenylsilyloxy)-1,1,1-trifluoropropan-2-ylcarbamate a white solid (342).