Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1=[O:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]1>>[C:10]([CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:3]1=[O:13])([OH:12])=[O:11]
Reactant: N[C@H]1CCCCN(CC(=O)O)C1=O
Reactant: CCOC(=O)C(=O)CCc1c[nH]c2ccccc12
Product: CCOC(=O)C(CCc1c[nH]c2ccccc12)N[C@H]1CCCCN(CC(=O)O)C1=O

Procedure:
In the same manner react the 3-(S)-amino-1-carboxymethylperhydroazepin-2-one with ethyl 4-(3-indolyl)-2-oxobutyrate to obtain 1-carboxymethyl-3-(S)-[(1-ethoxycarbonyl-3-(3-indolyl)propyl)amino]perhydroazepin-2-one. Standard alkaline hydrolysis (as in Example 3) of this material yields 1-carboxymethyl-3-(s)-[(1-carboxy-3-(3-indolyl)propyl)amino]perhydroazepin-2-one. Alternatively, esterification in HCl-ethanol affords 1-ethoxycarbonylmethyl-3-(S)-1-(1-ethoxycarbonyl-3-(3-indolyl)lpropyl)amino]perhydroazepin-2-one.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:17])([CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Br:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[CH3:16][C:8]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[Br:18])([CH3:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1C(C)(C)N
Reactant: CC(C)(C)C(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccccc1C(C)(C)NC(=O)C(Br)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (150 ml), α,α,2-trimethylbenzylamine (7.5 g) and triethylamine (6 g), and α-bromo-tert-butylacetyl chloride (10.2 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 13.8 g of N-(α,α,2-trimethylbenzyl)-α-bromo-tert-butylacetamide. M.P., 166.5°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH2:8][C:9]#N)[CH:7]=1.[CH3:12]I.[H-].[Na+].Cl.C[N:18]([CH3:21])C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([C:8]([CH3:12])([CH3:9])[C:21]#[N:18])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC#N
Reactant: CI
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1C(C)(C)C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5.25 g of (5-fluoro-2-methylphenyl)acetonitrile and 5.25 ml of methyl iodide are dissolved in 70 ml of dimethylformamide and mixed with 2.7 g of sodium hydride (80%) for 2.5 hours while being cooled with ice. After 3 hours at 0° C. and 16 hours at room temperature, it is mixed with ice water and ethyl acetate, acidified with 1 M hydrochloric acid, and the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. 6.1 g of 2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile is obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.Cl.C(N=C=NCCCN(C)C)C.O.O[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.C(N(C(C)C)C(C)C)C.C1(N)CCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:29][CH:33]1[CH2:34][CH2:35][CH2:36]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC1)c1ccc2cc(Br)ccc2c1
Yield: 72.7 %

Procedure:
By reactions similar to those in Reference Example 2, using 6-bromo-2-naphthoic acid (1.01 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.92 g), 1-hydroxy-1H-benzotriazole monohydrate (0.735 g; HOBt), dimethylformamide (16 ml), N-ethyldiisopropylamine (0.62 g) and cyclobutylamine (0.45 g), the title compound (0.89 g) was obtained as colorless needle crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:25](OCCC(C)C)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:11]=[C:9]2[C:8]([CH:12]=[N:25][NH:10]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of 5-tert-butyl-2-methylaniline (2.48 g, 15.2 mmol) in CHCl3 (40 ml) at 0° C. was slowly added acetic anhydride (3.3 ml, 34.9 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Potassium acetate (446 mg, 4.55 mmol) was added followed by slow addition of isoamyl nitrite (4.4 ml, 32.6 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc and washed with water, sat'd NaHCO3 and brine then dried over MgSO4 and concentrated. The residue was dissolved in THF/MeOH (1:1, 40 mL) and 10% NaOH (4.5 mL) was added. The reaction mixture was stirred at room temperature for 10 min then neutralized with 1.0 M HCl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to afford 1.02 g (39%) of 6-tert-butyl-1H-indazole as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.03 (s, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.48 (s, 1H), 7.29 (dd, J=8.7, 1.5 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>ClCCl>[C:30]([CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:34])#[N:31]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: N#CCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 98.9 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 mmol) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 5.67 g (55 mmol) of cyanoacetyl chloride [Org. Syn. Col. Vol. V p. 171] gives 14.7 g of 6-[4-(cyanoacetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>280°.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(CC)CC>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:28][CH2:27]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 18.9 mg (0.07 mmol) 2-Morpholin-4-yl-5-nitro-benzoyl chloride, 16.5 mg (0.084 mmol) 1-(2-Chloro-phenyl)-piperazine and 34 ul (0.245 mmol) NEt3 in 2 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 2 ml CH3CN/MeOH/HCOOH 2/2/1 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 23.2 mg (77%) of the title compound.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)#[C:2][CH2:3][CH2:4][CH3:5].[CH3:22][O:23][C:24]1[CH:45]=[CH:44][C:27]([C:28](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([O:17][CH2:16][C@H:15]2[O:18][C@@H:11]([N:10]3[CH:19]=[C:6]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:21])[NH:8][C:9]3=[O:20])[CH2:12][C@@H:13]2[OH:14])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]2[CH:44]=[CH:45][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 54.5 %

Procedure:
To 20.4 g (69.3 mmol) of 5-(1-pentynyl)-2'-deoxyuridine in 300 mL of dry pyridine was added 22.8 g of 4,4'-dimethoxytrityl chloride. The reaction was stirred for 17 h at room temperature and then concentrated. The residue was taken up in CH2Cl2 and washed twice with 0.5% aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Purification of the crude product by column chromatography afforded 21.9 g (52.9% yield) of product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10].[Cl:24]C1C=CC(S(N[C@H](CC#C)C(O)=O)(=O)=O)=CC=1>>[CH3:23][O:22][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NCC(OC)OC

Procedure:
Using the same procedure describe for the synthesis of 39, (R)-2-(4-chlorobenzenesulfonamido)pent-4-ynoic acid afforded the title compound. 1H NMR (400 MHz, CDCl3): δ 2.43 (m, 2H), 2.71 (s, 3H), 2.85 (s, 1H), 2.89 (s, 3H), 2.96 (m, 2H), 3.98 (t, 7.1 Hz, 3H), 4.15 (t, 5.5 Hz, 1H), 7.65(d, 8.0 Hz, 2H), 7.80 (d, 8.0 Hz, 2H), 7.97 (s, 1H), 8.11 (t, 5.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.N12CCN(CC1)CC2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C(OCC)(=O)C.CCCCCCC>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:4][O:3]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC1(C)OC[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (60.00 g, 454.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (63.67 g, 567.6 mmol) in ethyl acetate 600 mL) at 15° C. was added 4-chlorobenzenesulfonyl chloride (100.6 g, 476.7 mmol) and the resulting cloudy solution stirred for 2 h before being warmed to room temperature. The resulting solution was stirred at room temperature for 4 h before cold water (300 mL) was added and the resulting mixture stirred at room temperature overnight. The mixture was diluted with heptane (600 mL) and the organic layer was separated and washed with water (3×600 mL). The mixture was concentrated under vacuum to provide a yellow oil which was treated with heptane (200 mL). The mixture was concentrated to remove any remaining ethyl acetate and heptane (500 mL) was added once more to induce crystallization. The thick white suspension was filtered, washed with heptane, and suction dried to provide 4-chloro-benzenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (129.93 g, 93.3%, 98.9% pure HPLC, 99.89% e.e) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:4]=1[NH2:5].C(O)=O.[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[C:17]1=O)[CH2:23]2>C1(C)C=CC=CC=1>[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH:17]1[NH:5][C:4]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:3]=1[O:2][CH3:1])[CH2:23]2
Reactant: COc1cc(C)cc(OC)c1N
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COc1cc(C)cc(OC)c1NC1C2CC3CC(C2)CC1C3
Yield: 52 %

Procedure:
2.1 g of 2,6-dimethoxy-4-methylaniline are dissolved in 10 ml of toluene, 0.5 ml of formic acid is then added to this solution and the mixture is heated to gentle reflux, under inert atmosphere, and 0.93 g of 2-adamantanone, dissolved in 10 ml of toluene, is added dropwise at this temperature. The reaction mixture is heated at reflux for 48 hours, is then evaporated to dryness and the residue is taken up in 30 ml of 2N hydrochloric acid. The insoluble white crystals are filtered and discarded. The acidic filtrate is extracted with dichloromethane. The organic extracts are washed with a 5% aqueous sodium bicarbonate solution and then with water and the organic phases are then dried over anhydrous sodium sulphate. Evaporation leaves a colourless residue which is purified by flash chromatography on a column of silica gel, eluent: toluene/ethyl acetate 7/3 (v/v) in order to obtain N-(2-adamantyl)-2,6-dimethoxy-4-methylaniline; M.p.=100° C., Yield 52%.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14]C1C=CC=C2C(NC(=O)C=12)=O)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:27]N>C(O)C>[CH3:1][N:2]([CH2:12][CH2:13][CH2:14][NH2:27])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: CN(CCCc1ccccc1)CCCc1cccc2c1C(=O)NC2=O
Solvent: O
Solvent: CCO
Product: CN(CCCN)CCCc1ccccc1

Procedure:
To a solution of 3.49 (10.37 mM) of 3-[N-methyl-N-(3-phenylpropan-1-yl)amino]propan-1-ylphthalimide in ethanol (50 ml) was added 1.5 ml (30.92 mM) of hydrazine monohydrate at room temperature and the mixture was refluxed for 40 minutes. The solid that formed was filtered off and the filtrate was concentrated. The residue was diluted with water, made strongly basic with sodium hydroxide, and, then, extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[CH3:14][Sn](C)(C)C.C(Cl)(Cl)Cl>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 74.1 %

Procedure:
To a solution of 7-bromo-5-nitroindoline (0.65 g, 2.7 mmol) in 10 mL of DMF were added tetramethyltin (1.0 mL, 7.3 mmol) and bis(triphenylphosphine) palladium(II) chloride (0.10 g) in a portion and resulting mixture was stirred in sealed tube for 12 h at 140° C. The reaction mixture was concentrated in vacuo, providing a dark oily residue which was subjected to column chromatography (CHCl3, neat) to yield 0.35 g (2.0 mmol, 74%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15]O)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>ClCCl.O>[C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15][Br:50])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl{6-[(2,2-dimethylpropanoyl)amino]-4-(2-hydroxyethyl)pyridin-3-yl}acetate (2.30 g, 6.84 mmol) with imidazole (0.558 g, 8.20 mmol) in dichloromethane (50 mL) was treated with triphenylphosphine (1.79 g, 6.84 mmol) and carbon tetrabromide (2.72 g, 8.20 mmol). The reaction mixture was allowed to stir at room temperature for 2 h, then was diluted with water and the layers separated. The organic layer was washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4), filtered and concentrated. The residue was filtered through a short silica plug (20% EtOAc:hexanes eluent) to afford tert-butyl{4-(2-bromoethyl)-6-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}acetate which was used immediately in the next step. LC/MS (M+1)+=398.9;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16]Br)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12.[CH3:21][N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][N:25]2[CH2:26][CH2:27][CH2:28][N:22]([CH3:21])[CH2:23][CH2:24]2)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12
Reactant: N#CC1=C(CBr)Nc2n[nH]cc2C1c1ccccc1Cl
Reactant: CN1CCCNCC1
Product: CN1CCCN(CC2=C(C#N)C(c3ccccc3Cl)c3c[nH]nc3N2)CC1
Product: Cl

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and N-methylhomopiperazine in the same manner as in Example 1076.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[N:12][OH:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:11]([Cl:14])=[N:12][OH:13])=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Br)c2nsnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (Example 5.4) (16.65 g) in dimethylformamide (150 ml) was added N-chlorosuccinimide (“NCS”) (10.34 g). The reaction mixture stirred at ambient temperature for 16 hours. Water (750 ml) was added to the reaction mixture and the solids were isolated by filtration to obtain 7-bromo-N-hydroxy-benzo[1,2,5]thiadiazole-4-carbimidoyl chloride (15.77 g) as a yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12](C(OC)=O)=[N:13][CH:14]=2)[O:3]1.[CH3:20][Mg]Br.C([O:25][CH2:26][CH3:27])C>C1COCC1>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:19])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([C:26]([OH:25])([CH3:27])[CH3:20])=[N:13][CH:14]=2)[O:5]1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Mg]Br
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (Frontier, catalog No. M2012) (1.25 g, 4.75 mmol) in THF (48 mL) was added a solution of methyl magnesium bromide in ethyl ether (3.0 M, 12 mL, 36 mmol) via syringe at 0° C. with an ice water bath under dry N2. The reaction mixture was added at 0° C. for 30 minutes and then the ice-water bath was removed. After stirring at room temperature for 30 minutes, the reaction mixture was poured into saturated NH4Cl solution (300 mL) and followed by addition of 100 mL of EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and evaporated to afford crude title compound that was used directly in the next step reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30]([O:32]C)=[O:31])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+:35]>O1CCCC1.CO>[CH2:23]([O:22][CH2:21][CH2:20][C@@H:19]([N:14]1[C:15](=[O:18])[CH2:16][CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[C:30]([O-:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+:35]
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])[C@@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A solution of 2.01 g (4.40 mmol) of 4-((S)-3-benzyloxy-1-methoxycarbonyl-propyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 12 ml of tetrahydrofuran/methanol (1:1) was treated at 0° C. with 4.43 ml (4.40 mmol) of 1 M aq. lithium hydroxide solution, and kept 3 h at this temperature. The reaction was evaporated, dissolved in acetonitrile and evaporated again (3×) to give 1.94 g (98%) of the titled compound as light yellow foam. MS: 439.2 (M−H−).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>>[CH2:30]([CH:24]1[C:25](=[O:26])[O:27][CH:21]([CH2:20][CH2:19][CH:14]2[CH:13]3[C:12](=[CH:11][CH:10]([CH3:29])[CH2:9][CH:8]3[O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][CH:15]2[CH3:18])[CH2:22][CH:23]1[OH:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: Cl
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)C(Cc4ccccc4)C(=O)O3)C21
Reaction time: 0.25 h

Procedure:
After 15 minutes, 202 mg (0.50 mmol) of mevinolin are added and the reaction mixture is kept at −77° C. for 30 minutes. Then 171 mg (1.0 mmol) benzyl bromide are added. After 2 hours the reaction is let come to room temperature and poured onto 0.1 N aqueous HCl. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is purified by silica gel chromatography (diethyl ether/hexane 2/1) to afford the desired product as a colorless oil.