Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]([OH:23])([CH3:22])[CH3:21])[C@H:12]([CH3:24])[N:11]1[C:25](=[O:35])[CH2:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C:25]([N:11]1[C@@H:10]([CH2:9][OH:8])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]([OH:23])([CH3:21])[CH3:22])[C@@H:12]1[CH3:24])=[O:35]
Reactant: C[C@H]1c2cccc(C(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(C(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (0.054 g, 100 μmol) in THF (1.0 mL). Add tetrabutylammonium fluoride (0.11 mL, 110 μmol, 1M in THF). Stir 30 min. Add saturated ammonium chloride solution and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 10-100%) to give the title compound as a white foam (0.03 g, 71 μmol). MS (m/z): 422 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([O:8]2)[CH2:6]1)(=[O:4])=[O:3].[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH:9]1[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]1[OH:8])=[N+:13]=[N-:14]
Reactant: CS(=O)(=O)N1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a stirred solution of rac-3-methanesulfonyl-7-oxa-3-aza-bicyclo[4.1.0]heptane (0.92 g, 5.19 mmol, Example 303) in dimethylformamide (20 mL), sodium azide (550 mg, 8.46 mmol) was added and the mixture was stirred at 80° C. for 6 hours. The mixture was cooled and poured into water and extracted with ethyl acetate (3×10 mL). The extracts were combined, washed with water, brine and dried with MgSO4. The solvent was removed to give the desired product as colorless oil. 304 mg, 30.4%. The compound was used directly for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:12][CH2:11][C:10]1[S:9][CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ncsc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncsc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
4-Ethoxycarbonyl-5-hydroxymethylthiazole (282 mg) was dissolved in 5 ml of DMF, 123 mg of imidazole and 250 mg of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 374 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:15]([CH3:16])=[CH:14][S:13][CH:12]=1)[C:5]([OH:7])=O.[NH2:17][C:18](=[N:30]O)[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[F:29]>>[F:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[C:18]1[N:17]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([C:11]3[C:15]([CH3:16])=[CH:14][S:13][CH:12]=3)=[C:2]([CH3:1])[CH:3]=2)[O:7][N:30]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(C(N)=NO)c(F)c1
Reactant: Cc1cc(C(=O)O)ccc1-c1cscc1C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4cscc4C)c(C)c3)n2)c(F)c1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 6 (116.2 mg; 0.50 mmol) and Intermediate 2 (106.1 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was suspended in ACN, filtrated and washed with cHex dried under vacuo, affording the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 8.35-8.30 (m, 1H), 8.17 (d, J=1.3 Hz, 1H), 8.08-8.01 (m, 2H), 7.95 (dd, J=11.0, 1.3 Hz, 1H), 7.46-7.42 (m, 2H), 7.35 (dd, J=3.2, 1.1 Hz, 1H), 3.93 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H). LC/MS (Method B): 409.1 (M+H)+. HPLC (Method A) Rt 6.06 min (Purity: 93.6%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:33]([N:35](CC)[CH2:36]C)C.CNC.O1CCCC1>C(Cl)Cl>[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:35]([CH3:36])[CH3:33])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Under ice-cooling, 1 g (9 mmol) of methanesulfonyl chloride was added dropwise to a solution of 3 g (8 mmol) of 1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 2.46 g (24 mmol) of triethylamine in methylene chloride. After the reaction mixture was stirred at room temperature for 1 hour, 20 ml of 2N dimethylamine-tetrahydrofuran solution was added, and the mixture was stirred overnight. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and it was purified by silica gel column chromatography to obtain 700 mg (22%) of the title compound.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(2,3-dichlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 25, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: BrC1C(C2C=CC(SC)=CC=2)=C([C:12]([O:14][CH3:15])=[O:13])C2C=1C=CC=CC=2.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:43]=[C:42]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41]3)[C:35]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[C:35]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:36]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=[CH:37]3)[C:43]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Reactant: COC(=O)c1c2cccccc-2c(Br)c1-c1ccc(SC)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c2cccccc-2c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1

Procedure:
Methyl 3 -bromo-2-(4-methylthiophenyl)azulene-1-carboxylate: To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (2.00 g) in CCl4 (20.0 ml) was added N-bromosuccinimide (1.26 g) and α,α'-azobis(isobutyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The mixture was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/Et2O, 100:1) to give the title compound (2.40 g) as violet crystals; mp 98°-100° C.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH3:11])[CH:4]=1>C(O)(=O)C.O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:1])=[C:5]([CH3:11])[CH:4]=1
Reactant: Br
Reactant: Cc1cc(Br)ccc1CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)ccc1CBr
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Hydrobromic acid (conc., 2 eq.) was added to a stirred solution of the alcohol from step 1 (1 eq.) in acetic acid (0.22M). The mixture was stirred at 50° C. for 12 h, cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water, aqueous sodium hydrogen carbonate (3×), brine, dried over MgSO4, filtered and concentrated to afford the desired benzyl bromide as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:4][C@H:3]1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=1)=[O:22].[H-].[Na+].Br[CH2:40][C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42]>CN(C)C=O>[C:43]([C:41]([CH2:40][N:8]1[C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:4][C@@H:3]([NH:20][C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=2)=[O:22])[C:2]1=[O:1])=[O:42])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)[C@H](NC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)CN2C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)[C@H](NC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)CN2C1CCCCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
(R)-1-(2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea (500 mg) was dissolved in N,N-dimethylformamide (5 ml), the solution was cooled to internal temperature 5° C. Under argon atmosphere, 60% sodium hydride (49 mg) was added, the mixture was stirred at internal temperature 5° C. for 30 minutes. Bromomethyl tert-butylketone (218 mg) was added thereto, stirred at internal temperature 5° C. for one hour. The reaction mixture was poured into ice-water, extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform), to thereby obtain 200 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].O>N1C=CC=CC=1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=[N:15][OH:16])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1coc(-c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=Cc1coc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of 2-phenyloxazole-4-carboxaldehyde (2.18 g, 12.5 mmol) in pyridine (25 ml) was added hydroxylamine hydrochloride (0.96 g, 13.8 mmol) under stirring at room temperature. After 1 hour the mixture was poured into water (200 ml) and the resulting solids were collected, washed with water and dried under vacuum. 2.02 g (10.8 mmol) of the titled compound was obtained: mp 145°-147° C.; IR (KBr) 3195, 3075, 3035, 2850, 1646, 1555, 1486, 1445, 1431 cm-1 ; 1H NMR (270 MHz, CDCl3) d 8.87 (brs,1H), 8.51 (s,1H), 8.09-8.05 (m,2H), 7.68 (sy,1H), 7.52-7.47 (m,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]2=O)([O-:3])=[O:2].ClS([N:23]=C=O)(=O)=O.CO>C(#N)C>[NH2:23][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cc(N)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C

Procedure:
To a suspension of methyl 1,4-dihydro-6-nitro-4-oxo-2-quinolinecarboxylate (3.72 g, 15 mmol) obtained in Example 131, Step 2 in acetonitrile (50 ml) was added chlorosulfonyl isocyanate (1.30 ml, 15 mol) and the mixture was refluxed under heating for 1 hr. The reaction mixture was cooled to room temperature and methanol was added, which was followed by concentration under reduced pressure. To the residue was added 2 mol/l aqueous sodium carbonate solution to allow suspending and the insoluble matter was collected by filtration. The insoluble matter was dried under reduced pressure at 80° C. to give methyl 4-amino-6-nitro-2-quinolinecarboxylate as crude brown crystals (3.23 g). This compound was used in the next reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 3.85 g (7.00 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-4-[(t-butyldiphenylsiloxy)methyl]-1,1'-biphenyl (Step D) in 25 mL of dry tetrahydrofuran under a nitrogen atmosphere was added by syringe 10.5 mL (0.530 mmol) of a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred for two hours then diluted with 700 mL of diethyl ether. The mixture was washed with water (3×150 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), then dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give an oil which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (55:45) to afford 2.02 g (92%) of the product as a white solid (mp 89°-93° C.). 1H NMR (200 MHz, CDCl3): δ1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.18-7.45 (m, 8H). FAB-MS: calculated for C19H23NO3 313; found 314 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: NCC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a 25 mL round bottomed flask cooled to 0° C. was added 2-amino-4,6-di-chloro-5-formyl-pyrimidine (192 mg, 1.0 mmol, 1.0 eq.), THF (10 mL), DIEA (0.34 mL, 2.0 mmol, 2.0 eq.), and 2-amino-N-(3-trifluoromethyl-phenyl)-acetamide (245 mg, 1.0 mmol, 1.0 eq.). The reaction mixture was warmed to RT and allowed to stir overnight before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude product as a solid. The solid was then rinsed with 5:95 EtOAc:Hexanes to give pure 2-(2-Amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (159 mg, 43%). LC/MSD (HP Series 1100 MSD): Expected MW: 373, Observed M+H, 374.0, Retention time: 1.45 min. ANALYTICAL HPLC: >95%, Retention time: 4.15 min (8 minute run). 1H-NMR (d6-DMSO): 10.5 (s, 1H), 9.9 (s, 1H), 9.42 (t, 1H), 8.08 (s, 1H), 7.80 (d, 1H), 7.59 (t, 1H), 7.42 (d, 1H), 4.40 (d, 2H) ppm.
Reaction SMILES: [C:1](Cl)(Cl)=O.[CH:5]1[C:10]([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)[CH:6]=1.[N:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>>[CH:5]([N:18]([CH:19]([CH3:20])[CH3:1])[CH2:23][CH3:22])([CH3:10])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: c1ccncc1
Product: CCN(C(C)C)C(C)C

Procedure:
In the second preferred activating procedure, the T-CA is treated with a phosgene equivalent (approx. 1.1 equivalent), e.g., 4-nitrophenylchloroformate, and a tertiary amine (approx. 1.1 equivalent), e.g., diisopropylethylamine, in an aprotic solvent, e.g., pyridine, at between 0° and 25° C. for between 10 min and 2 hrs to give the active T-CA linker.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCC3C3CCN(C)CC3)cc1OCC2
Temperature: 110 °C
Yield: 16 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 (300 mg, 0.80 mmol), 1-methyl-4-pyrrolidin-2-ylpiperidine (338 mg, 2.00 mmol), NaOtBu (232 mg, 2.40 mmol) and Pd(PtBu3)2 (20 mg, 0.04 mmol) in toluene (6 mL) was heated at 110° C. for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (C18, gradient 10-65% MeOH in H2O) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 141 (20 mg, 16%) as a white solid. LCMS: RT 2.91 min [M+H]+ 462.4. 1H NMR (DMSO, 400 MHz): δ 8.18 (1H, d, J=8.95 Hz), 7.87 (1H, s), 7.77 (1H, s), 6.49 (1H, dd, J=9.03, 2.41 Hz), 6.13 (1H, d, J=2.36 Hz), 5.94-5.93 (1H, m), 4.45-4.40 (4H, m), 3.74 (1H, s), 3.45-3.43 (1H, m), 3.14-3.11 (1H, m), 2.78 (2H, s), 2.12 (3H, s), 1.99-1.72 (5H, m), 1.71-1.51 (3H, m), 1.47 (6H, dd, J=6.60, 1.90 Hz), 1.33-1.31 (3H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C1COCC1.CCOC(C)=O>[C:12]1([O:11][C:9](=[O:10])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 124.2 %

Procedure:
To a solution of 2-aminopyridine (3.0 g) in dry THF (30 mL) was added phenyl chloroformate (1.0 g, 0.8 mL) dropwise at 0° C., followed by another batch of phenyl chloroformate (1.0 g, 0.8 mL). The reaction mixture was allowed to warm to rt. After 18 h, the mixture was diluted with EtOAc (100 mL) and washed with satd. aq. NaHCO3 (20 mL). The organic layer was dried (MgSO4) and concentrated. The residue was chromatographed to give a white solid (1.7 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: Cc1cc(Cc2cccc(Br)c2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3cccc(Br)c3)oc(C)c2C)cc1C(C)C
Yield: 65.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.02 g, 4.32 mmol, RN-117439-59-5), oxalyl chloride (0.415 mL, 4.75 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.556 mL, 4.75 mmol) and 2-(3-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.32 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.36 g (65%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ 1.17 (d, 12H), 1.80 (s, 3H), 2.20 (s, 3H), 3.28 (septet, 2H), 3.74 (s, 3H), 3.87 (s, 2H), 7.06 (d, 1H), 7.19 (d, 1H), 7.24 (s, 1H), 7.38 (dd, 1H), 7.46 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH2:8]([CH:11]1[CH2:15][N:14]([CH2:16][C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)[C:13](=[O:41])[CH2:12]1)[CH2:9][CH3:10]>C(#N)C>[O:41]=[C:13]1[CH2:12][CH:11]([CH2:8][CH2:9][CH3:10])[CH2:15][N:14]1[CH2:16][C:17]1[N:18]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])[CH:19]=[N:20][CH:21]=1
Reactant: CCOC(=O)CBr
Reactant: CCCC1CC(=O)N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cc2cncn2CC(=O)OCC)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, ethylbromoacetate (560 μl, 4.95 mmol) is added to a solution of 4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x45 (1.5 g, 3.3 mmol) in 10 ml of acetonitrile. The mixture is stirred at 40° C. for 3 h, 1.65 mmol of ethylbromoacetate is added and stirring is pursued for 48 h at room temperature. The mixture is concentrated in vacuo, 20 ml of a 1/1 mixture of acetic acid and water is added and the mixture is stirred at room temperature overnight. The mixture is filtered, the solvent is evaporated and the residue is dissolved in 25 ml of diluted HCl (pH 1). The aqueous phase is washed with CH2Cl2, basified to pH 10 by addition of solid Na2CO3 and extracted three times with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by tin layer chromatography on preparative plates (CH2Cl2/EtOH: 90/10 (v/v)) to give 275 mg of ethyl {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate (30%). Ethyl {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetate hydrochloride x49 is obtained by treatment with a solution of HCl in Et2O and recrystallization from CH3CN/AcOEt.