Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1.O>O1CCCC1>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCO)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1

Procedure:
2-hydroxyethyl-4-(4-tert-butyldimethylsilyloxybutyl)benzene (0.3 g, 0.97 mmol)is dissolved in dry tetrahydrofuran and to it is added sodium hydride (24 mg, 1 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.164 g, 1 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](/[CH:14]=[C:15](\[S:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])/[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:17])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:36]I.[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](/[CH:14]=[C:15](\[S:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])/[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:17])=[CH:10][N:11]2[CH3:36])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: COc1cc(C(=O)/C(=C/c2c[nH]c3cc(NC(C)=O)ccc23)SCC(O)CO)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)/C(=C/c2cn(C)c3cc(NC(C)=O)ccc23)SCC(O)CO)cc(OC)c1OC
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Compound 125 (300.0 mg) obtained in Example 125 was dissolved in a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), and methyl iodide (93.6 mg) and then sodium hydride (26.4 mg, 60% mineral oil dispersion) were added thereto, followed by stirring for 1.5 hours. The reaction solution was subjected to partitioning between chloroform and water, and the organic layer was successively washed with water and a saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude crystals were washed with chloroform and recrystallized from a mixed solvent of ethanol, N,N-dimethylformamide, and water to give Compound 126 (249.7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Na+].[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[OH-].[Na+].CCOCC>[C:18]1([CH2:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(Oc1ccc(NC(=O)Cc2ccccc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 57.4 %

Procedure:
FIG. 2C illustrates a general reaction scheme for preparing the Group I 2-[4-(arylacetamido)phenoxy]-2-methyl propionic acids. In accordance with the illustrated scheme, 1 g (0.005 mol) of 2-(4-aminophenoxy)-2-methyl propionic acid is dissolved with stirring in 10 ml of water containing 0.41 g (0.1 mol) of NaOH. To this solution, 0.79 g (0.005 mol) of phenyl acetyl chloride in 5 ml of tetrahydrofuran (THF) is gradually added over a period of about 15 minutes. After the addition is complete the pH of the reaction mixture should be alkaline (if not a few drops of 2N NaOH is added to assure alkalinity). The reaction mixture is continuously stirred for 1 hour. Thereafter, the THF is evaporated in vacuo, and the solution is then diluted with 5 ml water and acidified with concentrated hydrochloric acid. The product is extracted with ethyl ether (2×20 ml), washed with water (3×20 ml), and then dried over anhydrous MgSO4. Upon addition of petroleum ether to the ether solution, 0.9 g (56% yield) of the 2-[4-(phenylacetamido)phenoxy]-2-methyl propionic acid product precipitates as a pale brown solid, mp 173°-175° C.
Reaction SMILES: Br[C:2]1[C:3](CNC2C[C@H](C)O[C@H](C)C2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=3)[C:7]=1[N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C.O>C(O)(C(F)(F)F)=O>[F:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:27]1[CH:26]=[N:25][N:6]3[C:7]([NH2:8])=[CH:2][CH:3]=[N:4][C:5]=13)=[CH:37]2
Reactant: C[C@@H]1CC(NCc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C[C@H](C)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc2c(-c3cnc4ccc(F)cc4c3)cnn12
Reaction time: 2 h

Procedure:
To a 6-bromo-5-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ylamino)methyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (69.3 mg, 0.09 mmol) in TFA (2 ml) was added few drops of water and stirring continued for 2 h at room temperature. LC/MS showed no starting material remaining. TFA along with water was rotoevaporated. This crude compound was submitted to the analytical group for purification to afford the desired 6-bromo-5-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ylamino)methyl)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine. LCMS: 3.157 mins, m/z=499.0 (MH+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH2:19][O:20][C:21]([NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C:26](O)=[O:27])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[NH2:44][C:45]1[S:49][C:48]([SH:50])=[N:47][N:46]=1>C1COCC1>[C:13]1([CH2:19][O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C:26]([NH:44][C:45]2[S:49][C:48](=[S:50])[NH:47][N:46]=2)=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Reactant: Nc1nnc(S)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1)Nc1n[nH]c(=S)s1
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
Carbonyldiimidazole (0.879 g, 5.42 mmol) is added to a solution of (R)-β-[[(phenylmethoxy)carbonyl]amino]benzenepropanoic acid (1.08 g, 3.62 mmol) in 25 mL THF under N2 at room temperature and allowed to stir for 0.5 hours. Diisopropylethylamine (0.63 mL, 3.6 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (0.482 g, 3.62 mmol) are added and the reaction is stirred at ambient temperature for 18 hours. The reaction is concentrated in vacuo, diluted with 50 mL CH2Cl2, and washed with (3×25 mL) 1 M citric acid. The organic phase is dried (Na2SO4), combined with the precipitate that formed in the aqueous phase, absorbed onto silica gel and chromatographed (2-5% MeOH/CH2 Cl2). The precipitate which formed in the fractions containing product is collected and dried to afford 0.217 g product as white needles.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:25][O:26][C:27](=[O:56])[C@H:28]([CH2:52][CH2:53][S:54][CH3:55])[NH:29][C:30](=[O:51])[CH2:31][N:32]([CH2:44][C@@H:45]([NH2:50])[CH:46]([CH3:49])[CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.CCN(CC)CC>CN(C=O)C>[CH3:25][O:26][C:27](=[O:56])[C@H:28]([CH2:52][CH2:53][S:54][CH3:55])[NH:29][C:30](=[O:51])[CH2:31][N:32]([CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[CH2:44][C@@H:45]([NH:50][C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C@@H:46]([CH3:49])[CH2:47][CH3:48]
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
4-Imidazoleacetic acid (0.064 g, 0.395 mmol), dissolved in DMF (5 mL) was treated with HOBT (0.053 g, 0.40 mmol), EDC (0.076 g, 0.40 mmol), and N-[2(S)-amino-3-methylpentyl)-N-(1-naphtylmethyl)glycyl-methionine methyl ester hydrochloride (0.175 g, 0.329 mmol). The pH was adjusted to 7.5 with Et3N (0.15 mL, 1.1 mmol) and the mixture was stirred at ambient temperature for 24 h. After concentration, and the mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 solution (10 mL). The aqueous layer was washed with EtOAc (1×20 mL). The organic layers were combined, washed with brine (1×10 m), dried (Na2SO4), filtered and concentrated to give 0.170 g of crude product. Purification by chromatography (silica gel, eluting with 1 to 3% methanol in methylene chloride) gave 0.080 g of pure product. 1H NMR (CD3OD); δ8.30-8.25 (d, 1H, J=9 Hz), 7.91-7.86 (d, 1H, J=6 Hz), 7.85-7.79 (d, 1H, J=9 Hz), 7.56 (s, 1H), 7.55-7.38 (m, 4H), 6.9 (s, 1H), 4.37-4.27 (m, 1H), 4.23-4.04 (m, 3H), 3.67 (s, 3H), 3.49 (ABq, 2H), 3.25 (ABq, 2H), 2.90-2.70 (m, 2H), 2.21-1.97 (m, 2H), 1.95 (s, 3H), 1.88-1.74 (m, 1H), 1.64-1.46 (m, 2H), 1.44-1.25 (m, 1H), 1.14-0.98 (m, 1H), 0.93-0.77 (m, 6H).
Reaction SMILES: N12CCN(CC1)CC2.[F:9][B-:10]([F:13])([F:12])[F:11].F[B-](F)(F)F.F[N+:20]12[CH2:27][CH2:26][N+:23]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:24][CH2:25]1)[CH2:22][CH2:21]2.CS(Cl)(=O)=O.F[B-](F)(F)F.[Na+]>O1CCCC1.C(#N)C>[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:31][S:28]([N+:23]12[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]1)[CH2:21][CH2:22]2)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)[N+]12CC[N+](F)(CC1)CC2
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CS(=O)(=O)[N+]12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Fluoro-4-methanesulfonyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazabicyclo[2.2.2]octane (11 g, 10 mmol) in tetrahydrofuran (100 mL) is reacted with methanesulfonyl chloride (11.5 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The filtrate is evaporated to afford 1-methanesulfonyl-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:9])([F:8])[C:4]([O:6][CH3:7])=[O:5].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.CC(O)=O.C1COCC1>[CH:10]1([NH:1][CH2:2][C:3]([F:9])([F:8])[C:4]([O:6][CH3:7])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C(F)(F)CN
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)(F)CNC1CCCC1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a round bottom flask was added methyl 3-amino-2,2-difluoropropanoate (570 mg, 3.24 mmol), THF (20 mL), cyclopentanone (0.433 mL, 4.87 mmol), and HOAc (1 mL). To this mixture was added sodium triacetoxyborohydride (1.06 g, 5 mmol) portionwise. The reaction was left to stir overnight. It was then added slowly to a stirring solution of ice, NaHCO3 (sat.), and EtOAc. The aqueous layer was further extracted with EtOAc, the organic extracts combined, dried over MgSO4, filtered and concentrated to yield the desired product as clear syrup (400 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (td, J=13, 6 Hz, 2H) 1.43 (d, J=8 Hz, 1H) 1.47-1.70 (m, 4H) 1.77 (dt, J=12, 6 Hz, 2H) 3.12 (t, J=6 Hz, 1H) 3.19 (t, J=14 Hz, 2H) 3.88 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[NH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21]>C1COCC1>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])=[O:5]
Reactant: Nc1cc(OCc2ccccc2)ccc1O
Reactant: O=C(O)CBr
Solvent: C1CCOC1
Product: O=C(CBr)Nc1cc(OCc2ccccc2)ccc1O
Yield: 505.7 %

Procedure:
Bromoacetic acid (13.9 g, 0.01 mole) and dicyclohexyldicarbodiimide (DCCD, 20.6 g, 0.01 mole) were added at room temperature under stirring to the amine ((b), 21.5 g, 0.01 mole) in THF (200 ml). After 1 hour the reaction mixture was filtered and the liquid evaporated to dryness under vacuum. The residue was crystallized from acetic acid (50 ml) to give the bromoamide ((c), 17 g, 50%) as white prisms. The product strusture was confirmed by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C=O)C.N1C=CN=C1.[C:38]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])([CH3:40])[CH3:39]>CCOC(C)=O.O>[Si:42]([O:26][C@@H:24]([CH3:25])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:27])[C:12]([NH:14][CH2:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A 500 mL round bottomed flask was charged with (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-N-(2-oxo-2-phenylethyl)butanamide (7.87 g, 20.4 mmol) and DMF (200 mL) then cooled to 0° C. Imidazole (6.94 g, 102 mmol) and tert-butylchlorodimethylsilane (9.22 g, 61.2 mmol) were added and the mixture was stirred and warmed to room temperature overnight. Water (200 mL) was added to the mixture followed by EtOAc (200 mL) and the phases partitioned. The organic phase was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated to furnish the title compound as a white solid (8.2 g, 80%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.97 (d, J=8 Hz, 2H), 7.44-7.66 (m, 1H), 7.40 (d, J=8 Hz, 1H), 6.42 (d, J=8 Hz, 1H), 5.43 (d, J=6 Hz, 1H), 4.77 (dd, J=6, 8 Hz, 2H), 4.79 (dd, J=5, 15 Hz, 2H), 4.70 (d, J=5, 15 Hz, 1H), 4.52-4.58 (m, 1H), 3.85-4.89 (m, 1H), 2.39 (s, 3H), 1.24 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[CH2:24]1[O:26][CH:25]1[CH2:27][OH:28]>O1CCOCC1.O>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:24][CH:25]([OH:26])[CH2:27][OH:28])=[CH:8][CH:7]=1)=[O:5])[CH3:21]
Reactant: OCC1CO1
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCC(O)CO)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
The 2-(4-diethylcarbamoylbenzyl)phenol (355 mg) obtained in Reference Example 1(d) was dissolved in a mixed solution of dioxane (3.6 ml) and water (3.6 ml), added with 1 N aqueous sodium hydroxide (63 μl) and glycidol (0.12 ml) and stirred at 90° C. for 18 hours. The reaction mixture was added with water (30 ml) and extracted twice with dichloromethane (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 263 mg of the title compound. Yield: 59%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=2)[CH3:13])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[CH2:33][C:34](Cl)=[O:35].[H-].[Na+].Cl.N>C(Cl)Cl.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([N:14]2[C:34](=[O:35])[CH2:33][O:24][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=3)[CH2:15]2)[CH3:13])=[CH:7][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cccc(Cl)n1
Agent: Cl
Agent: N
Agent: [H-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cc1ccc(OCCO)cc1)N1CC(c2cccc(Cl)n2)OCC1=O

Procedure:
1 g (0.0285 mol) of N-[2-(4-(2-hydroxyethoxy)-phenyl)-1-methyl-ethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)-ethanamine is dissolved in 40 ml of methylene chloride, 0.28 g (0.00285 mol) of triethylamine are added and then 0.322 g (0.00285 mol) of chloroacetyl chloride are added dropwise thereto with stirring in an ice bath. The reaction solution is stirred at ambient temperature for 40 minutes and evaporated down. The residue is dissolved in 10 ml of dimethylformamide, 110 mg (0.00234 mol) of 50-55% sodium hydride in oil are added and the resulting mixture is stirred for 30 minutes at ambient temperature. It is then carefully decomposed with 30 ml of water, acidified with 2N hydrochloric acid and then made alkaline with 2N ammonia. The product is extracted with methylene chloride, dried over sodium sulphate and concentrated by evaporation. The residue is purified over a silica gel column using ethyl acetate as eluant.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][Br:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(C(C)=O)cc(Cl)c(CBr)c1Br
Temperature: 25 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (3.3 g, 12 mmol), N-bromosuccinimide (2.2 g, 13 mmol), and benzoyl peroxide (0.15 g, 0.60 mmol) in carbon tetrachloride (50 mL) was heated at reflux overnight. The mixture was cooled to room temperature and concentrated. The resulting residue was diluted with ethyl acetate and washed with water. The organic layers were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step. LCMS calculated for C10H10Br2ClO2 (M+H)+: m/z=355.1. found: 355.1.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C1(=O)[N:27]([C:28]([N:45]2C(=O)C3=CC=CC=C3C2=O)([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:29][O:30][O:31][O:32][OH:33])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:45][C:28]([NH2:27])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:29][O:30][O:31][O:32][OH:33]
Reactant: CCCCCCCCCCCC(OOOOO)(N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCC(N)(N)OOOOO
Temperature: 25 °C
Reaction time: 3 h
Yield: 173.6 %

Procedure:
A solution of diphthalimide (Step 4: 60 g), hydrazine hydrate (15 g) and ethanol (500 mL) is heated at 100° C. with stirring for 3 hrs. The reaction mixture is cooled to room temperature and filtered. The solid is washed with cold ethanol. The combined filtrate is concentrated under vacuum in a rotary evaporator to afford 33 g of yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([CH3:12])[CH3:11].O.NN.[OH-].[K+].O>C(O)COCCOCCO.C(OCC)(=O)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)CC(=O)c1ccccc1N
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Solvent: CCOC(C)=O
Product: CC(C)CCc1ccccc1N
Temperature: 210 °C
Yield: 72.1 %

Procedure:
A solution comprising 8.0 g (0.045 mol) of 1-(2-aminophenyl)-3-methylbutan-1-one (X-1), 6.8 g (0.135 mol) of hydrazine hydrate and 7.6 g (0.135 mol) of potassium hydroxide in 90 ml of triethylene glycol is heated at 210° C. for 6 h. For work-up, water and ethyl acetate are added at room temperature. The organic phase is again washed with water, dried over magnesium sulphate and concentrated under reduced pressure. Purification by column chromatography (cyclohexane/ethyl acetate 3:1) gives 5.3 g (71.5% of theory) of [2-(3-methylbutyl)-phenyl]amine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[OH-].[NH4+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C)c(C(=O)O)c(N)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(C(N)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4,6-dimethyl-benzoic acid (0.35 g, 2.08 mmol) in anhydrous THF (10 mL) was added EDCl (0.80 g, 4.17 mmol), HOBt (0.80 g, 5.22 mmol) and N-methyl-morpholine (0.7 mL, 6.24 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then ammonium hydroxide (50% v/v, 2.5 mL) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure. Water (50 mL) was added, and the mixture was extracted with dichloromethane (2×100 mL). The combined organic phase was washed with water, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-amino-4,6-dimethyl-benzamide. Yield: 0.20 g (59%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11](=O)[C:6]2=[N:5][N:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[F:1][C:2]([F:14])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11](=[S:24])[C:6]2=[N:5][N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCCn2c1nnc2C(F)(F)F
Product: FC(F)(F)c1nnc2n1CCNC2=S
Temperature: 25 °C

Procedure:
A mixture of 173 mg (0.84 mmol) of 3-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one, 703 mg (1.68 mmol) of Lawesson's Reagent, and 18 mL of xylenes was stirred at reflux for 4.5 h. After being cooled to room temperature, the solvent was decanted off, and the residue was washed with diethyl ether. The resulting solid was dried and purified by flash chromatography (20-50% acetone in hexanes) to give the title compound as a greenish-yellow solid. LC-MS 223 (M+1).