Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)C>[N:16]1([CH2:2][CH2:3][CH2:4][C:5]2[CH:15]=[CH:14][CH:13]=[C:7]3[C:8]([NH:10][C:11](=[O:12])[C:6]=23)=[O:9])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCN3CCOCC3)cccc21

Procedure:
3-Bromopropylphthalimide (536 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])CC)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.N[C@H:32]1CC[C@H](C2C=CC(C(N(CC)CC)=O)=CC=2)C[CH2:33]1.C(N)CCC>>[NH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:27][CH2:28][CH2:32][CH3:33])=[O:23])=[CH:29][CH:30]=2)[CH2:16][CH2:17]1
Reactant: CCN(CC)C(=O)c1ccc([C@H]2CC[C@H](N)CC2)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)cc1
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc([C@H]2CC[C@H](N)CC2)cc1

Procedure:
The compound of the title is obtained by carrying out the procedure as described in Preparation 8 (iii) and (iv), but using n-butylamine instead of diethylamine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:12]1[CH:23]=[CH:22][C:15]2[O:16][C:17]([CH3:21])([CH3:20])[O:18][CH2:19][C:14]=2[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1.C(N(CC)C(C)C)(C)C.C(#N)C>O.C(OCC)C>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:12]1[CH:23]=[CH:22][C:15]2[O:16][C:17]([CH3:20])([CH3:21])[O:18][CH2:19][C:14]=2[CH:13]=1)[OH:11])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Reactant: NS(=O)(=O)c1cccc(CCCOCCCCCCCBr)c1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCCOCCCc3cccc(S(N)(=O)=O)c3)Cc3ccccc3)ccc2O1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A mixture of (1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (55.8 g), 3-{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (63.65 g), N,N-diisopropylethylamine (55 ml) and acetonitrile (200 ml) was stirred and heated under N2 at reflux for ca 21 h. The mixture was cooled to room temperature then diethyl ether (1000 ml) and water (500 ml) were added and the mixture stirred. The organic phase was washed with water (500 ml), then saturated brine (500 ml) and dried (Na2SO4). The solution was concentrated and the product purified by chromatography on flash silica gel (1000 g), eluting with petroleum ether:ethyl acetate (ratios ranging successively from 4:1 to 1:1) to give the title compound (97.7 g)-LC RT=1.54 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([F:20])[CH:22]=2)=[CH:7][C:6]=1[F:8]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 94.5 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 3.0 g (8.6 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.9 g (11 mmol) of 3-fluoro-4-methoxyphenylboronic acid (Example 4, Step 3). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 3.19 g (94%) of 1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 159.2-159.7° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.87 (s, 3H), 6.63-6.85 (m, 3H), 7.16-7.32 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 392 (49), 313 (15), 298 (48), 269 (100), 249 (79). Anal. Calc'd for C20H15F3O3S (0.26 ethyl acetate): C, 60.85; H, 4-0.15; F, 13.71. Found: C, 61.33; H, 3.90; F, 13.40.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH:2]=[CH2:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C([O-])=O.[CH2:37]([O:40][C:41]1[CH:42]=[C:43]([CH:70]=[C:71]([F:73])[CH:72]=1)[CH2:44][CH:45]([NH3+:69])[CH:46]([OH:68])[CH2:47][N:48]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][CH3:57])[CH:51]=1)[CH:38]=[CH2:39]>C(Cl)Cl.CCOC(C)=O>[CH2:61]([O:60][C:58](=[O:59])[N:48]([CH2:47][CH:46]([OH:68])[CH:45]([NH:69][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:5](=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][CH2:14][CH3:15])[CH2:44][C:43]1[CH:70]=[C:71]([F:73])[CH:72]=[C:41]([O:40][CH2:37][CH:38]=[CH2:39])[CH:42]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][CH3:57])[CH:51]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: C=CCOc1cc(F)cc(CC([NH3+])C(O)CN(Cc2cccc(CC)c2)C(=O)OCc2ccccc2)c1
Reactant: C=CCN(CCC)C(=O)CCCC(=O)O
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1cc(F)cc(CC(NC(=O)CCCC(=O)N(CC=C)CCC)C(O)CN(Cc2cccc(CC)c2)C(=O)OCc2ccccc2)c1

Procedure:
A solution of [4-(3-Allyloxy-5-fluoro-phenyl)-3-tert-butoxycarbonylamino-2-hydroxy-butyl]-(3-ethyl-benzyl)-carbamic acid benzyl ester (1.84 g, 3.03 mmol) in 20% TFA/DCM (30 mL) is prepared and stirred for 1 hour. The reaction mixture is concentrated in vacuo yielding a white solid (2.12 g). Peptide coupling is performed by preparing a solution of 4-(allyl-propyl-carbamoyl)-butyric acid (0.060 g, 2.82 mmol) in CH2Cl2 to which is added EDC (0.74 g, 3.84 mmol) and HOBT (0.52 g, 3.84 mmol) under N2, with stirring. To this solution is added a solution of TEA (1.43 mL, 10.24 mmol), 1-(3-Allyloxy-5-fluoro-benzyl)-3-[benzyloxycarbonyl-(3-ethyl-benzyl)-amino]-2-hydroxy-propyl-ammonium trifluoro-acetate (1.59 g, 2.56 mmol) dissolved in CH2Cl2 (15 mL). Upon complete reaction the mixture is diluted with EtOAc, washed with NaHCO3 and then 1N HCl. The mixture is then neutralized with NaHCO3, and then 0.5N NaOH, treated with activated charcoal, dried with MgSO4, filtered, concentrated in vacuo, yielding a yellow oil. Purification is achieved via flash chromatography using 75% EtOAc/Hexanes. Calculated mass for C41H52FN3O6+H1: 702.3918. Accurate mass found for C41H52FN3O6+H1: 702.3916.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.[F:12][C:13]([F:27])([F:26])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][N:4]1[C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:6][C:2]([O:1][CH2:14][C:13]([F:27])([F:26])[F:12])=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: COC(=O)c1cc(O)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(F)(F)F)nn1C
Temperature: 100 °C

Procedure:
A solution of 200 mg (1.28 mmol) of methyl 3-hydroxy-1-methyl-5-pyrazolecarboxylate (for preparation see above) in 10 ml of N,N-dimethylformamide is admixed with 254 mg (2.56 mmol) of 2,2,2-trifluoroethyl-4-methylbenzenesulphonate and 138 mg (2.56 mmol) of potassium carbonate and the reaction mixture is heated at 100° C. for five hours and afterstirred at room temperature for two days. The reaction mixture is added to water and extracted several times with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo on a rotary evaporator. This gives 500 mg of methyl 1-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate (50% strength, 82%).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:27])=[O:22])[CH3:26])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-alanine methyl ester hydrochloride using the procedure described in Method 3. The resulting methyl ester was deesterified via hydrolysis using LiOH in THF/water to provide the title compound as a solid, mp=160.5-162.5° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Brc1ccccn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromopyridine
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:41])[C@@H:24]([NH2:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:41])[CH:24]([NH:40][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH:15]([CH3:17])[CH3:16])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: CC(C)C(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 48.2 %

Procedure:
A solution of the product from Example AC ((S)-2-[(azepane-1-carbonyl)-amino]-3-methyl-butanoic acid) (0.50 g, 2.07 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.67 g, 2.07 mmol) were coupled according to the procedure described in Example AH. The crude reaction product was purified by chromatography (silica gel, EtOAc) to give the title compound as a white foam (0.55 g, 48%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[C:18](=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH2:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Add 5.0 g of 1-benzhydryl-2-benzimidoylazetidine to an ice cold suspension of 1.16 g of lithium aluminium hydride in 135 ml of dry ether. Stir the mixture at 0° C. for 15 minutes, then allow the mixture to warm to room temperature and continue stirring for 18 hours. Cool the suspension to 0° C. and cautiously quench by the successive addition of 1.25 ml of water, 1.75 ml of 10% aqueous sodium hydroxide, and 3.5 ml of water. Stir, filter and wash the precipitate with ether. Combine the ether washes with the original filtrate and wash the resultant solution successively with water and brine. Dry over anhydrous sodium sulfate, and remove ether in vacuo.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[O:17][CH:18]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)[CH2:19][CH2:20][CH2:21][N:22]1[CH2:29][CH:28]2[O:30][CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23]1>CC#N.C(Cl)(Cl)Cl>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH:18]([O:17][C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:19][CH2:20][CH2:21][N:22]2[CH2:29][CH:28]3[O:30][CH:24]([CH2:25][N:26]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:27]3)[CH2:23]2)=[CH:38][CH:37]=1)#[N:36]
Reactant: CCN=C=O
Reactant: COc1ccc(OC(CCCN2CC3CNCC(C2)O3)c2ccc(C#N)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCNC(=O)N1CC2CN(CCCC(Oc3ccc(OC)c(OC)c3)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of ethyl isocyanate (18.8 mg, 0.25 mmol) in MeCN (2 mL) was added, together with K2CO3 (34.5 mg, 0.25 mmol), to a solution of 4-[1 -(3,4-dimethoxyphenoxy)-4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-butyl]benzonitrile (Preparation H; 109.4 mg, 0.25 mmol) in chloroform (0.5 mL). The reaction mixture was stirred at rt for 4 days before being added to a solid phase extraction plug (SiO2, 0.5 g). The plug was washed with CHCl3:MeCN (2.5 mL of 80:20), and the product was finally eluted with CHCl3:MeOH (3×2.5 mL of 95:5) to give the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:9]=2[N:10]=1>C(OCC)(=O)C>[CH3:16][O:15][C:11]1[C:9]2[N:10]=[C:6]([N:5]=[C:1]=[O:2])[S:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cccc2sc(N=C=O)nc12

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-4-methoxybenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 4-methoxybenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:55])[CH2:53][CH3:54])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:55][C@H:52]([CH2:51][O:50][Si:33]([C:46]([CH3:47])([CH3:49])[CH3:48])([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:53][CH3:54])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: CC[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S)-1-(t-butyldiphenylsilyloxymethyl)propylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-1-(t-butyldiphenylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.52 g, yield 79%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][Mg+].[Br-]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH3:17]
Reactant: C[Mg+]
Reactant: COc1cc2c(cc1Br)C(=O)CCC2(C)C
Agent: [Br-]
Product: COc1cc2c(cc1Br)C(C)=CCC2(C)C
Yield: 94 %

Procedure:
Following General Procedure A 7-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthanlen-1-one (Compound 92,1.0 g, 3.5 mmol) was reacted with MeMgBr to give 0.93 g (94%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[C:12][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: C#Cc1cnc(N)c(C#N)c1C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)cnc(N)c1C#N

Procedure:
A solution of 1.6 grams (0.010 mole) of 2-amino-3-cyano-4-methyl-5-ethynylpyridine, 3.8 grams (0.014 mole) of 4-trifluoromethylphenyl iodide (commercially available), 3.5 grams (0.035 mole) of triethylamine, 0.3 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.3 gram (catalyst) of copper(I) iodide in 75 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-[(4-trifluoromethylphenyl)ethynyl]pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Product: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]1([CH2:22][C:23](=O)[C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:22]([C:23]1[C:24](=[O:25])[N:8]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(Nc2ncccc2N)c1
Reactant: O=C(O)C(=O)Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Yield: 53.8 %

Procedure:
A mixture of 3-amino-2-[(m-tolyl)amino]pyridine (299 mg) and phenylpyruvic acid (246 mg) in ethanol (5 ml) was refluxed for 2 hours. The mixture was cooled and the precipitates were collected and washed with ethanol to give 2-benzyl-3-oxo-4-(m-tolyl)-3,4-dihydropyrido[2,3-b]-pyrazine (264 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19]C)C.B(Br)(Br)Br.CO>ClCCl>[CH3:1][O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19]
Reactant: CCOC(=O)CCCCN(CCc1cc(F)ccc1OC)Cc1ccc(C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCN(CCc1cc(F)ccc1O)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.6 g (5.84 mmol) of methyl 4-({(5-ethoxy-5-oxopentyl)[2-(5-fluoro-2-methoxy-phenyl)ethyl]amino}methyl)benzoate are dissolved in 50 ml of dichloromethane, the mixture is cooled to 0° C., and 19.3 ml (19.3 mmol) of a 1N solution of boron tribromide in dichloromethane are added dropwise. The solution is stirred at 0° C. for one hour. 50 ml of methanol are slowly added dropwise at 0° C., and the reaction mixture is heated at reflux overnight. The mixture is cooled and the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with sodium carbonate, the aqueous phase is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue is chromatographed over silica gel (cyclohexane:ethyl acetate (5:1) to ethyl acetate: methanol (9:1)).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:10]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)#[N:9]>N1C=CC=CC=1>[C:8]([C:10]([O:37][C:1](=[O:3])[CH3:2])([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([CH:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:19])=[CH:15][CH:16]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)#[N:9]
Reactant: N#CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C#N)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Yield: 61.3 %

Procedure:
) Acetic acid anhydride (0.03 mol) was added dropwise to a solution of (±)-N-[4-(cyanohydroxyphenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.010 mol) in pyridine (80 ml), stirred at 0° C. The reaction mixture was stirred for 4 days at RT. The solvent was evaporated. The residue was dissolved in EtOAc and washed with water. The organic layer was separated, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2/CH3OH 92/8). The desired fractions were collected and the solvent was evaporated, yielding 2.7 g (61%) of (±)-[cyano-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]-phenylmethyl]acetate. (compound 83)