Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2]1.[C:21]([CH2:24][N:25]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32][N:31]([CH2:37][C:38]([OH:40])=[O:39])[CH2:30][CH2:29][N:28]([CH2:41][C:42]([OH:44])=[O:43])[CH2:27][CH2:26]1)([OH:23])=[O:22].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][N:34]1[CH2:35][CH2:36][N:25]([CH2:24][C:21]([OH:23])=[O:22])[CH2:26][CH2:27][N:28]([CH2:41][C:42]([OH:44])=[O:43])[CH2:29][CH2:30][N:31]([CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:33]1
Reactant: c1ccc(COCCCCCCCCCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)CCCCCCCCCOCc2ccccc2)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
28.73 g (103.92 mmol) of 1,2-epoxy-11-benzyloxyundecane and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) are dissolved in a mixture of 50 ml of dioxane/80 ml of water and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 12.22 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=O.[F:41][C:42]([F:54])([F:53])[C:43]1[CH:44]=[C:45]([NH:49][C:50]([NH2:52])=[O:51])[CH:46]=[CH:47][CH:48]=1.[C:55]([O:61][CH2:62][CH:63]=[CH2:64])(=[O:60])[CH2:56][C:57]([CH3:59])=O>CC(OC)(C)C>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH:26]2[C:56]([C:55]([O:61][CH2:62][CH:63]=[CH2:64])=[O:60])=[C:57]([CH3:59])[N:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:42]([F:53])([F:54])[F:41])[CH:44]=3)[C:50](=[O:51])[NH:52]2)=[C:29]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH:30]=1)#[N:33]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C=O
Reactant: C=CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: COC(C)(C)C
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)CC
Temperature: 90 °C

Procedure:
The reaction was carried out under argon. Triethyl phosphate (0.718 g, 3.9 mmol) and diphosphorus pentoxide (0.511 g) were stirred at 40° C. overnight. The mixture was then diluted with MTBE (30 ml), and 4-formyl-3-(ethylsulfonyl)benzonitrile (0.88 g, 3.94 mmol), 1-[3-(trifluoromethyl)phenyl]urea (0.805 g, 3.94 mmol) and allyl acetoacetate (0.841 g, 5.91 mmol; 1.5 eq.) were added. The mixture was then stirred under reflux for 4 h. The reaction mixture was then concentrated by distillative removal of MTBE and subsequently heated at 90° C. for a further 2 h. For work-up, residual solvent was removed under reduced pressure, and the residue was suspended in MTBE (20 ml) and then filtered off with suction. The solid was washed with MTBE (10 ml). This gave 1.34 g (42% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][CH2:21][C:22]1[C:23](=[O:42])[C:24]([C:38](OC)=[O:39])=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH:27]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:38]([C:24]1[C:23](=[O:42])[C:22]([CH2:21][O:20][CH3:19])=[CH:27][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)[N:25]=1)=[O:39]
Reactant: CNOC
Reactant: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added AlMe3 (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 5-(methoxymethyl)-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (3.08 g, 9 mmol) in CH2Cl2 (30 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (1.99 g, 60% yield) as an off-white solid: mp 157-159° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.53 (3H, s), 3.67 (3H, s), 4.50 (2H, d, J=1.1 Hz), 7.62-7.71 (2H, m), 7.79-7.85 (1H, m), 7.90 (1H, s), 8.39 (1H, t, J=1.1 Hz). Anal. Calcd for C16H16F3N3O4: C, 51.75; H, 4.34; N, 11.32. Found: C, 51.77; H, 4.25; N, 11.24.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17](Cl)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].[F:24][C:25]([F:39])([F:38])[O:26][C:27]1[CH:28]=[C:29]([C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+].[F-].[K+]>CS(C)=O.O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([N:36]2[CH:37]=[C:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:25]([F:24])([F:38])[F:39])[CH:28]=3)[N:34]=[CH:35]2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(Cl)n1
Reactant: FC(F)(F)Oc1cccc(-c2c[nH]cn2)c1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(-n2cnc(-c3cccc(OC(F)(F)F)c3)c2)n1
Temperature: 25 °C
Yield: 122.2 %

Procedure:
A solution of 2-(2,6-dichloro-pyrimidin-4-ylamino)-4-methylpentanoic acid (3-ethoxypropyl)amide (1.5 gram), 4-(3-trifluoromethoxyphenyl)-1H-imidazole (0.99 gram), K2CO3 (1.7 gram) and KF (0.24 gram) in dimethylsulfoxide (40 ml) was heated to 100° C. for 17 hours. The solution was cooled to room temperature, taken up in water, and extracted three times with ethyl acetate. The etyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (toluene/acetone 4/1) provided 2.8 g of 4-methyl-2-{6-chloro-2-[4-(3-trifluoromethoxyphenyl)-imidazol-1-yl]-pyrimidin-4-ylamino}-pentanoic acid (3-ethoxypropyl)amide as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[CH3:27][C:28]([CH3:32])([CH3:31])[CH:29]=[O:30].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.C1CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[C:12]([CH:29]([OH:30])[C:28]([CH3:32])([CH3:31])[CH3:27])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: CC(C)(C)C=O
Reactant: O=C(NCc1cccc(Cl)c1)c1occc(=O)c1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (300 mg) obtained in Example 10, Step 1 and 2,2-dimethylpropionaldehyde (9 ml) in tetrahydrofuran (9 ml) was added dropwise 1.5 M lithium diisopropylamide-tetrahydrofuran/cyclohexane solution (4.5 ml) under nitrogen at −78° C. After stirring at the same temperature for 2 hr, the cooling bath was removed and 1N aqueous hydrochloric acid (15 ml) and ethyl acetate (25 ml) were added, and the mixture was warmed to room temperature. The organic layer was separated from the aqueous layer and extracted with ethyl acetate (25 ml). The combined organic layer was dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[C:43]([O:47][C:48](=[O:65])[NH:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:9])=[C:52]([C:57]#[C:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:51]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of oxane-4-carboxylic acid (45 mg, 0.34 mmol), HATU (162 mg, 0.43 mmol) and DIPEA (43 μl, 0.25 mmol) in DMF (1 ml) is stirred at RT for 30 minutes. Tert-butyl-N-[5-amino-6-(2-phenylethynyl)pyridin-2-yl]carbamate B5a (60 mg, 0.19 mmol) is added and stirring continued for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 40 mg (49%). HPLC-MS: M+H=422; tR=1.73 min (*Method—5).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12]CC)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18]>C(OCC)(=O)C>[OH:12][C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]2[C:15](=[O:23])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=[C:2]2[N:11]=1
Reactant: CCOc1nc(Cl)nc2ccccc12
Reactant: COC(=O)c1ccccc1N
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2nc2nc(O)c3ccccc3n12
Temperature: 25 °C

Procedure:
To the 2-chloro-4-ethoxy-quinazoline (500 mg, 2.40 mmol) in a boiling tube was added methyl anthranilate (372 μL, 2.88 mmol). The mixture was heated with a hot air gun (approx. 400 deg C.) for 15 minutes before cooling to room temperature. The resulting crude product was suspended in ethyl acetate (10 mL) and heated to boiling. The mixture was then cooled and the pure off-white product isolated by filtration (257 mg).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:27][CH2:26][C@:5]2([NH:9][C@@H:8]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:13]=[CH:12][N:11]=3)[CH2:7][CH2:6]2)[C:4]1=[O:28].C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:31][N:9]1[C@:5]2([CH2:26][CH2:27][N:3]([CH3:2])[C:4]2=[O:28])[CH2:6][CH2:7][C@@H:8]1[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)N2)C1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CC[C@@]2(CC[C@H](c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)N2C)C1=O
Reaction time: 1 h

Procedure:
To a solution of (2R,5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one hydrochloride (which may be prepared as described in Example 52) (21 mg, 0.0500 mmol) in methanol (0.5000 mL) was added 3 meq of 3.7% formalin solution and sodium triacetoxyborohydride (16.21 mg, 0.0800 mmol) and the mixture was stirred for 1 h. The mixture was evaporated and partitioned between satd. aq. NaHCO3 (2 ml) and MDC (3×5 ml) and the residue purified on an SCX-2 cartridge (0.5 g) eluting with MeOH to 2% aq NH3 in MeOH to give (2R,5S)-1,7-dimethyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one, a clear oil (16.9 mg);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH2:21][CH:22]4[CH2:25][O:24][CH2:23]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.C(NC(C1N2CCOC3C=CC([C:48]#[C:49][C@@:50]([OH:58])([C:52]4[CH:56]=[C:55]([CH3:57])[O:54][N:53]=4)[CH3:51])=CC=3C2=NC=1C(N)=O)=O)(C)(C)C.CNC1COC1.CC1ON=C([C@](O)(C#C)C)C=1>>[OH:58][C@:50]([C:52]1[CH:56]=[C:55]([CH3:57])[O:54][N:53]=1)([CH3:51])[C:49]#[C:48][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH2:21][CH:22]4[CH2:25][O:24][CH2:23]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: NC(=O)c1nc2n(c1C(=O)NCC1COC1)CCOc1ccc(Br)cc1-2
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC(C)(C)C)n2CCO3)no1
Agent: C#C[C@@](C)(O)c1cc(C)on1
Agent: CNC1COC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCC4COC4)n2CCO3)no1
Yield: 2 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-N3-(oxetan-3-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide (prepared as described in the synthesis of (R)—N3-(tert-butyl)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing tert-butyl amine with 3-methylaminooxetane) was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (6.7 mg, 2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18](C)=O.C[S-].[Na+].CCCCCCC>C(OCC)(=O)C>[CH3:17][S:18][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1CNc1cccc(Cl)n1
Reactant: CS(C)=O
Agent: C[S-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CSc1cccc(NCc2ccccc2O)n1
Temperature: 90 °C

Procedure:
Introduced into a microwave tube are 300 mg (1.28 mmol) of 2-[(6-chloropyridin-2-ylamino)methyl]phenol, to which 5 ml of dimethyl sulphoxide and 448 mg (6.4 mmol, 5 eq) of sodium methanethiolate are added. The reaction mixture is heated for 16 h at 90° C. The reaction medium is diluted with 50 ml of ethyl acetate and then washed with 50 ml of a saturated ammonium chloride solution then 2×50 ml of distilled water. The organic phase is dried over magnesium sulphate then filtered and concentrated to dryness. The residue is purified by chromatography over 40 g of silica with, as eluent, heptane/ethyl acetate (7/3). The product obtained is put back into solution in ethyl acetate, heptane is added until the solution becomes cloudy, it is then cooled to 0° C. and filtered. 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1COCC1.C[Mg]Br.O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]([OH:12])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(Br)ccc1OCc1ccccc1

Procedure:
2-Benzyloxy-5-bromobenzaldehyde (5 g) was dissolved in anhydrous diethyl ether (20 mL) and THF (20 mL) and stirred at ambient temperature under argon while a solution of methyl magnesium bromide in ether (7.4 mL, 3M solution in ether) was added dropwise over 5 minutes. A white precipitate formed. After 30 minutes the mixture was poured onto a mixture of ice and water (300 mL). The aqueous mixture was extracted with ethyl acetate (3×250 mL), the organic extracts were washed with brine (100 mL) and dried (MgSO4). After removal of the solvent the residual pale yellow oil was purified by MPLC (eluting with dichloromethane on silica) to give 1-(2-benzyloxy-5-bromophenyl)-ethanol, (5.19 g, mp 76.7° C.).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]=[O:13])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)[C:16](N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=[O:17].Cl.[CH3:90]O>>[CH3:90][O:13][CH:12]([O:17][CH3:16])[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CO
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCc1ccc(CCC=O)cc1
Agent: Cl
Product: CCCc1ccc(CCC(OC)OC)cc1
Temperature: 0 °C

Procedure:
A reaction flask was charged with 3-(4-propyl-phenyl)-propionaldehyde (147 g, prepared as above), methanol (500 mL), and TMOF (90 g). The reaction mass was cooled to 0° C. and hydrochloric acid (37%, 1 g) was added in one portion. The reaction was exothermic and the temperature rose to 23° C. The reaction mass was quenched with sodium methoxide in methanol (25%, 10 g) and the solvent was removed by evaporation. The crude intermediate product 3-(4-propyl-phenyl)-propionaldehyde dimethylacetal was provided and confirmed by the NMR analysis. 3-(4-Propyl-phenyl)-propionaldehyde dimethylacetal was further treated with phosphoric acid (10 g) and pyridine (8 g) at 200° C. The reaction mass was aged for 4 hours, during which methanol was recovered in a Dean Stark trap. The reaction mass was then cooled and washed with aqueous sodium carbonate solution. Fractional distillation of the organic layer afforded the product 4-propyl 1-(3-methoxy-2-propen-1-yl)benzene (80 g), which had a boiling point of 101° C. at a pressure of 3 mmHg.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])([O-:15])=[O:14]>CC(N(C)C)=O>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:8](=[O:9])[C@:7]([OH:12])([CH3:11])[CH2:6][Br:5])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])([O-:15])=[O:14]
Reactant: C[C@](O)(CBr)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C[C@](O)(CBr)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Thionyl chloride (8.6 g, 72 mmol) was added dropwise under argon to a solution of bromoacid R-131 (11.0 g, 60 mmol) in 70 mL of DMA at −5 to −10° C. The resulting mixture was stirred for 2 h under the same conditions. A solution of 4-nitro-3-trifluoromethyl-aniline (12.4 g, 60 mmol) in 80 mL of DMA was added dropwise to the above solution, and the resulting mixture was stirred overnight at room temperature. The solvent was removed on Rotavapor using high vacuum oil pump; the residue was diluted with saturated NaHCO3 solution, and extracted with ethyl ether (100 mL×3). Combined extracts were dried over anhydrous Na2SO4, filtered through Celite, and purified by flash chromatography on silica gel, using methylene chloride as eluent to afford 18.0 g (80%) of the desired compound: mp 98100° C. (Rf=0.2, silica gel, CH2Cl2); 1H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H, NH), 8.54 (d, J=2.1 Hz, 1H, ArH), 8.34 (dd, J=9.0 Hz, J=2.1 Hz, 1H, ArH), 8.18 (d, J=9.0 Hz, 1H, ArH), 6.37 (s, 1H, OH), 3.82 (d, J=10.4 Hz, 1H, CHHa), 3.58 (d, J=10.4 Hz, 1H, CHHb), 1.48 (s, 3H, Me); 13C NMR (75 MHz, DMSO-d6) δ 173.6 (C═O), 143.0, 127.2, 123.2, 122.6 (q, J=33.0 Hz), 122.0 (q, J=271.5 Hz), 118.3 (q, J=6.0 Hz), 74.4, 41.4, 24.9; IR (KBr) 3344 (OH), 1680 (C═O), 1599, 1548 (C═C, Ar), 1427, 1363, 1161 cm−1; MS (ESI): m/z 370.8 (M)+; Anal. Calcd. for C11H10BrN2O4: C 35.60, H 2.72, N 7.55. Found: C 35.68, H 2.72, N 7.49.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of methyl 5-(N-t-butoxycarbonyl-N -methylamino)valerate (557 mg) in methanol (6 ml) and 1N sodium hydroxide solution (3.41 ml) was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo, and the residue was poured into water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified with 1N hydrochloric acid, and extracted with ethyl acetate (20 ml×3). The extract was collected and washed with water (40 ml×2) and brine (40 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 5-(N-t-butoxycarbonyl-N-methylamino)valeric acid (470 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC[C:16](OCC)=[S:17].[C:21]([O:25]Cl)(C)(C)[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][S:17][CH:22]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:4]=2)[NH:1][C:21]1=[O:25]
Reactant: CCOC(=S)CC
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2ccc(-c3ccccc3)cc21
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
A solution of 21.4 g. (0.13 mole) of 4-aminobiphenyl in 400 ml. of methylene chloride was cooled to -65° C. and treated with 17.0 g. (0.13 mole) of ethyl 2-methylthioacetate and then 14.2 g. (0.132 mole) of t-butylhypochlorite while maintaining the temperature below -60° C. The reaction mixture was stirred at -65° C. for 1.5 hr., treated with 1.33 g. (0.132 mole) of triethyl amine and allowed to warm to ambient temperature. The solution was washed twice with water and concentrated. The residue was dissolved in 200 ml. of methanol, 40 ml. of 3N hydrochloric acid was added, and the mixture was refluxed over night. The solution was concentrated until a solid began to precipitate. The mixture was cooled, and the solid was collected by filtration, recrystallized once from methanol and twice from benzene to yield 6.0 g. (18%) of product as a white solid, m.p. 170°-2° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:21](O)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C1COCC1>[CH3:24][C:22]([C:21]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([N:13]=[N:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:15][CH:16]=1)=[O:25])=[CH2:23]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
0.6 g of sodium hydride was added carefully to a 3 neck flask equipped with a condenser, addition funnel, and magnetic bar. 75 ml of anhydrous THF was added and the mixture stirred for 10 minutes. A solution of 4.0 g 4-(4-nitrophenylazo)aniline in 75 ml THF was added drop-wise and the flask stirred at 50° C. The temperature was raised to 95° C., and the mixture was refluxed for 6 hrs. The mixture was allowed to cool to room temperature and then 6.0 g of methacrylic acid in 20 ml THF was added drop-wise. The mixture was again refluxed for 8 hrs. The solution was cooled to room temperature. THF was evaporated to reveal a dark orange solid. The solid was washed thoroughly with dilute HCl and water. The product was recrystallized in 95% methanol. The yield was 56%.