Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]3)=[CH:10][CH:9]=2)=CC=1.BrC1C=C[C:25]([O:28]CC)=[CH:24]C=1>>[CH2:25]([O:28][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[CH:12][CH:13]=1)[CH3:24]
Reactant: C[C@@H]1CN(c2ccc(-c3ccc(F)cc3)cc2)CCN1
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(N2CCN[C@H](C)C2)cc1

Procedure:
The title compound was prepared following the procedure of Intermediate 22 but starting from 1-bromo-4-ethoxybenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a brown solid. M+(ESI): 221.3. HPLC (Condition A), Rt: 1.5 min (HPLC purity: 97.6%).
Reaction SMILES: [S-2:1].[Na+].[Na+].[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:18][CH2:19]Br)[CH2:15][CH2:16]Br>CN(C=O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8]3([CH2:18][CH2:19][S:1][CH2:16][CH2:15]3)[C:9](=[O:14])[NH:10][C:11]2=[CH:12][CH:13]=1
Reactant: O=C1Nc2ccc(Br)cc2C1(CCBr)CCBr
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Br)cc2C12CCSCC2
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
Sodium sulfide (292 mg, 3.75 mmol) was added to a solution of 5-bromo-3,3-bis(2-bromoethyl)-1,3-dihydro-2H-indol-2-one from Step B (532 mg, 1.25 mmol) in DMF (2 mL) and the solution heated to 50° C. After 2.5 h, the mixture was partitioned between CH2Cl2 (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=300 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([Li])CCC.[C:27](=[O:29])=[O:28]>C1COCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:6]1[CH:5]=[CH:4][C:3]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:2]([CH:7]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C=O
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(OCCN2CCOCC2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 21 %

Procedure:
A solution of 1-bromo-5-dimethoxymethyl-2-(2-morpholinoethoxy)benzene (3.11 g, 8.63 mmol) obtained in Step 3 in THF (40.0 mL) was cooled to −78° C., to which n-butyllithium (1.60 mol/L, 20.0 mL, 32.0 mmol) was added dropwise for 3 minutes, followed by stirring at −78° C. for 5 minutes. The reaction mixture was added with dry ice and was stirred for 3 hours while warming to room temperature. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was added with a 1 mol/L aqueous ammonium acetate solution (30 mL), was purified by HP-20 column chromatography (water, then acetonitrile/water=2/1), then crystallized from mixed solvent of ethyl acetate/hexane (1/1) to obtain 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid (0.58 g, 21%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH:6]=[C:5]2[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)(=[O:19])=[O:18].[CH:33]1([NH:36][C:37](=[O:55])[C:38]2[CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[C:41]([CH3:53])=[C:40]([F:54])[CH:39]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:33]1([NH:36][C:37]([C:38]2[CH:39]=[C:40]([F:54])[C:41]([CH3:53])=[C:42]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][CH:14]3[CH2:15][CH2:16]3)[CH:6]=[C:5]4[S:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)(=[O:19])=[O:18])[CH:43]=2)=[O:55])[CH2:35][CH2:34]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cn(CC3CC3)c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A solution of tert-butyl 4-{[6-bromo-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfonyl}piperazine-1-carboxylate (Example 47b, 0.890 g) in DMF (10 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.491 g), Pd-118 (0.030 g) and potassium carbonate (0.425 g). The mixture was stirred at 70° C. for 1 h. The cooled reaction mixture was diluted with water (100 mL), and extracted into ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography, elution with 10% ethyl acetate/DCM) to afford the subtitle compound (0.713 g) as beige foam, which was used without further analysis.
Reaction SMILES: [F:1][C:2]([F:15])([O:6][CH2:7][CH:8]1[CH2:12]OC(C)(C)[O:9]1)[CH:3]([F:5])[F:4].[Br:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[O:19].S(=O)(=O)(O)O>CC(C)=O>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1([CH2:17][Br:16])[O:9][CH:8]([CH2:7][O:6][C:2]([F:1])([F:15])[CH:3]([F:5])[F:4])[CH2:12][O:19]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CC1(C)OCC(COC(F)(F)C(F)F)O1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: FC(F)C(F)(F)OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Temperature: 120 °C

Procedure:
A mixture of 4-(1,1,2,2-tetrafluoroethoxy)methyl-2,2-dimethyl-1,3-dioxolane (6.8 g), 2-bromo-1-(2,4-dichlorophenyl)ethanone (6 g.), sulphuric acid (0.3 ml at 96%) is heated at 120° C. for 3 hours, the acetone being formed in the reaction being distilled off.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH2:12]C(N)=O>ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:12]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: NC(N)=O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1Br

Procedure:
588 mg of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanol and concentrated onto 364 mg of alumina on a rotary evaporator. The residue is irradiated in a microwave at 150° C. for a total of 60 min. After cooling, the residue is stirred with ethyl acetate and water, filtered, and the aqueous phase of the filtrate is separated. The organic phase is washed with a sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product is reacted further without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([O:15]CC)=[O:14].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
A mixture of ethyl 2-(5,6-dichloro-1H-indol-3-yl)acetate (120 mg, 0.44 mmol), LiOH (90 mg, 2.20 mmol) in THF (3 mL) and H2O (1 mL) was stirred at RT for 16 h. The solution was poured into water, adjusted pH to 3-4 with 1N HCl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the desired product (90 mg, 84.5% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[CH2:23]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 1.27 ml of allyl bromide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the product is obtained having a melting point of 146°-147°.
Reaction SMILES: I(Cl)(=O)=O.[I:5](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH3:28])[CH:22]=1.C(=O)([O-])[O-].[Ca+2]>ClCCl.CO>[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH3:28])[C:22]=1[I:5]
Reactant: Cc1cc(N)cc(C)n1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)c(I)c(C)n1
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Benzyltrimethylammonium dichloroiodate (6 g) was added to 4-amino-2,6-dimethylpyridine (2.1 g) and calcium carbonate (2.25 g) in dichloromethane/methanol (55 ml) (8:3 v/v) and the mixture was stirred for 16 hours. Solvent was removed by evaporation and the residue partitioned between 5% sodium metabisulphite solution and dichloromethane. The aqueous phase was separated and washed with dichloromethane. The aqueous phase was then basified with sodium carbonate and extracted with dichloromethane. The organic phase was washed with water, saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation and the residue purified by flash chromatography eluting with dichloromethane/methanol (9:1 v/v) to give 4-amino-2,6-dimethyl-3-iodopyridine (B) (1.7 g) as a light yellow solid, m.p. 103°-110° C.; NMR (CDCl3): 2.3(s,3H), 2.7(s,3H), 4.6(br s,2H), 6.3(s,1H); mass spectrum (chemical ionisation): 249 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:31])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28](O)=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:15][CH:14]=1.C([O:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)(C)(C)C>>[F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:31])[NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28]([N:41]4[CH2:42][CH2:43][CH2:44][C@H:40]4[C:39]([OH:45])=[O:38])=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(-c2nnc3c(C(=O)O)nccn23)cc1)Nc1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: O=C(Nc1ccc(-c2nnc3c(C(=O)N4CCC[C@H]4C(=O)O)nccn23)cc1)Nc1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared from 3-(4-(3-(2-(trifluoromethoxy)phenyl)ureido)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-8-carboxylic acid (61G) and L-proline tert-butyl ester by analogous procedure described in Example 61H. HPLC/MS (Method C): retention time=1.91-2.01 min (broad rotomer), [M+H]+=556.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=O)[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:30]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:30][C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Temperature: 140 °C
Yield: 56.3 %

Procedure:
A mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.6 mmol) and ammonium acetate (1.4 g, 18.2 mmol) in xylene (15 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (795 mg, 56%). m/z 391.8, 393.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCC(Oc2ncccc2OCCO)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 4-hydroxy-N-methylpiperidine (67 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 62 mg (0.25 mmol, 63%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Cl-:14]>>[Cl:14][CH2:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: [Cl-]
Reactant: Cc1nccc(C(F)(F)F)c1CO
Product: Cc1nccc(C(F)(F)F)c1CCl

Procedure:
3-Hydroxymethyl-2-methyl-4-trifluoromethylpyridine from step 1 above was converted to the chloride using the procedure given in step 2 of Example 3. The crude 3-chloromethyl-2-methyl-4-trifluoromethylpyridine was purified by pressurized silica gel column chromatography using 95:5 hexane:EtOAc as eluant. 3-Chloromethyl-2-methyl-4-trifluoromethylpyridine was obtained as a white solid (TLC Rf = 0.45 (9:1 hexane:EtOAc)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccccc1
Product: COc1ccc2c(-c3ccccc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenylboronic acid to give (6-methoxy-1-phenyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(Br)ccc1CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1cc(Br)ccc1CN1CCOCC1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
5-Bromo-2-bromomethylbenzonitrile (2.50 g, 9.1 mmol) is added portionwise to a stirred solution of morpholine (828 μL, 9.5 mmol) and triethylamine (1.27 mL, 9.1 mmol) in methanol (2 mL). After 4 hr, the solvent is removed and the residue is suspended in water that is made basic with sodium hydroxide and then extracted with ethyl acetate. The extract is dried, filtered, and concentrated to give 5-bromo-2-(morpholin-4-yl)methylbenzonitrile (1.90 g, 74%) as a cream solid.
Reaction SMILES: C[OH:2].[C:3]([NH:16][C@@H:17]1[C:23](=[O:24])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1)(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(Cl)Cl.N1C=CC=CC=1>[C:3]([NH:16][C@H:17]([C:23]([OH:22])=[O:24])[CH2:18][CH2:19][C:20]([OH:2])=[O:21])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CO
Reactant: CCCCCCCCCCCC(=O)N[C@H]1CCC(=O)OC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 8 h
Yield: 84.4 %

Procedure:
10.00 g (0.00892 mol) of mono-terminal carbinol-modified silicone was dissolved in 10.00 g of methylene chloride and 1.00 g of pyridine. 4.67 g (0.0150 mol) of lauroylglutamic acid anhydride was added to the reaction mixture, and then the mixture was stirred overnight. The reaction liquid was concentrated and separated after adding hexane and a 90% methanol aqueous solution. The hexane layer was concentrated to obtain 10.64 g (0.00753 mol) of lauroylglutamic acid-modified silicone.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:14])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:24])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:24][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)ncnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c(C)ncnc1Cl

Procedure:
30.6 g (0.16 mol) of ethyl (4-hydroxy-6-methylpyrimidin-5-yl)acetate, 17.8 g (0.18 mol) of triethylamine and 263.2 g (1.72 mol) of phosphorus oxychloride were heated at reflux for 4 hours. The excess phosphorus oxychloride was stripped off, the residue was taken up in dichloromethane, and the mixture was added dropwise to 500 ml of sodium bicarbonate solution and neutralized by addition of solid sodium bicarbonate. The organic phase was separated off, dried and concentrated to give 30.4 g (88.5% of theory) of a dark oil which was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.[Li]CCCC.[O:20]1[CH2:23][C:22](=[O:24])[CH2:21]1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:22]2([OH:24])[CH2:23][O:20][CH2:21]2)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH:6]=1
Reactant: O=C1COC1
Reactant: Cc1cn(COCC[Si](C)(C)C)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cn(COCC[Si](C)(C)C)c(C2(O)COC2)n1
Reaction time: 1 h

Procedure:
Into a 1000-mL three-neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 192.1, 9 g, 42.38 mmol) in tetrahydrofuran (200 mL). This was followed by the addition of n-BuLi (34 mL, 2.5 M in THF) dropwise at −78° C. and stirred for 1 h. To this was added a solution of oxetan-3-one (6.11 g, 84.79 mmol) in tetrahydrofuran (30 mL) dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C., then quenched with 50 mL of NH4Cl (sat.). The aqueous phase was extracted with 1×600 mL of ethyl acetate. The organic layer was washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 13 g (crude) of the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Clc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3Cc4cccc(Cl)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 33.7 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 115 mg of 4-chloroisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 70 mg of the target compound.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][NH2:20].Cl.C([O-])(=O)C.[Na+]>O.N1C=CC=CC=1>[CH3:18][N:19]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:20]1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CNN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 80 °C
Yield: 94 %

Procedure:
545.0 Grams (2.43 moles) of dibenzoylmethane and 533 ml. of pyridine are stirred together and heated to 80° C. 112 Grams (2.43 moles) of methylhydrazine are then slowly added to the mixture and a strong exothermic reaction ensues necessitating cooling of the mixture with a water bath. When addition is complete, the mixture is heated to reflux and maintained in this condition for 40 minutes. The mixture is then cooled to 30° C., poured into 19 liters of 3N HCl, filtered, and the solid collected. This is reslurried in 198 grams (2.43 moles) of sodium acetate dissolved in 19 liters of water. The mixture is filtered, water washed and air dried to give 535 grams of product, 94.5% yield, having melting point 58° C. to 59° C.
Reaction SMILES: [CH2:1]([NH:13][C@@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:32](Cl)(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C1COCC1>[CH2:1]([N:13]([CH:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16])[C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
100 g of N-dodecyl-β-D-glucopyranosylamine from Example 4 were dissolved in 765 ml of THF and, in the presence of 32 g of triethylamine, 80 g of stearoyl chloride were added dropwise with cooling.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:11]([C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2.C(N(CC)CC)C>>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:29]3[CH2:30][C@@H:25]4[CH2:31][C@H:28]3[CH2:27][O:26]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:20]([F:23])([F:22])[F:21]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CC(C)(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
180 mg (0.511 mmol) of (8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 76.32 mg (0.563 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 179 μl (1.28 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 15 min 4% B, t 18 min 4% B, t 33 min 10% B), 130 mg of (8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics: