Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[C:17](=O)([O:26]N1C(=O)CCC1=O)[O:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25]>C(#N)C>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:17]([O:18][N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[O:26])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CO[C@H]2OCC[C@H]21)ON1C(=O)CCC1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
In a glass-lined reactor 17.7 kg (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in acetonitrile (30%) was added, then 3.9 kg of triethylamine 9 kg of solid disuccinimidyl carbonate (DSC) was added in portions, while keeping the reaction temperature below 35° C. The reaction mixture was stirred at 20° C. for 3 hours. The temperature was lowered to 2° C. and 45 kg of ice-water was added to the reactor. Precipitation was observed and the precipitate was filtered off. The cake was dissolved in 41 kg of chloroform and the aqueous phase was separated. The solution was evaporated to dryness and 18.8 kg of petroleum ether was added to the reactor containing the residue. The mixture was stirred at 0-5° C. for 1 hour. The resulting white precipitation was filtered off and rinsed with about 2 kg of petroleum ether. 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione was obtained as an off-white solid, weight 3.69 kg (yield 39.9%, purity 68.7% by HPLC area, mobile phase: CH3CN/15 mmol/L Na2HPO4, pH 3.0 by H3PO4(35/65); speed: 0.8 mL/min; retention time: 7.730 min.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[F:13].[CH2:14]([O:16][C:17](=[O:22])[CH:18](Cl)[S:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([F:13])[CH:7]=1)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]2)[S:19][CH3:20])[CH3:15]
Reactant: CCOC(=O)C(Cl)SC
Reactant: Oc1cc(F)c2ncc(Br)cc2c1
Product: CCOC(=O)C(Oc1cc(F)c2ncc(Br)cc2c1)SC

Procedure:
In a similar procedure to Stage 2, Step 1 of Example 5, 3-bromo-8-fluoro-quinolin-6-ol was reacted with chloro-methylsulfanyl-acetic acid ethyl ester to give (3-Bromo-8-fluoro-quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:43]=[CH:42][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26](CC3C=CC(OC)=CC=3OC)[C:25](=[O:40])[C:24]2=[O:41])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C1(OC)C=CC=CC=1>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][C:25](=[O:40])[C:24]2=[O:41])=[CH:42][CH:43]=1)(=[NH:11])[NH2:13]
Reactant: COc1ccc(CN2CCN(CCCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(OCCCCN2CCNC(=O)C2=O)cc1
Reaction time: 0.5 h

Procedure:
In 3.4 ml of anisole was dissolved 1.7 g of 4-[4-(4-benzyloxycarbonylamidinophenoxy)butyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 6.8 ml of trifluoroacetic acid was added to the solution, followed by refluxing for 5 hours. After cooling, the solvent was distilled off under reduced pressure. To the resulting residue was added 10 ml of ethyl acetate, and stirred for 30 minutes, after which the precipitate was collected by filtration and dried to obtain 1.2 g of 4-[4-(4-amidinophenoxy)butyl]-2,3-dioxopiperazine trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1Cc1ccccc1
Yield: 73 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.69 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 24 mg of lithium hydride and 507 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 746 mg of 3-benzyl-2-[(4-chlorophenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (65%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 163 mg of 2-[N-benzyl-N-(4-chlorophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (14%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ccc1OCC2
Temperature: 105 °C
Yield: 80.3 %

Procedure:
10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 (0.057 g, 0.15 mmol), 2-fluoropyridin-3-ylboronic acid (0.026 g, 0.183 mmol), potassium acetate (0.059 g, 0.609 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.007 mmol), DMF (6 mL) and water (0.6 mL) were mixed. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir and heat at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (47 mg, 80%). MS (ESI(+)): m/z 391.1 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].O.[C:17](OCC)(=[O:19])[CH3:18]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[C:17]([O:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])(=[O:19])[CH3:18]
Reactant: O=C(O)C=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of 4-hydroxy-3-nitrocinnamic acid (prepared as described in Preparation 1) were dissolved in 30 ml of acetic anhydride. One drop of sulfuric acid was added to the solution, which was then stirred for 2 hours at room temperature. 50 ml of water were added the solution, and it was then stirred for a further 2 hours. At the end of this time, ethyl acetate was added, and the mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was mixed with toluene; the remaining acetic acid was removed by azeotropic distillation to obtain 10.2 g of the title compound as crystals.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 74.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.242 g, 1.22 mmol) was reacted with 2-azidoethanamine (0.105 g, 1.22 mmol) and triethylamine (0.246 g, 2.43 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-butylbenzamide (0.224 g, 75% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.4 Hz, 2H), δ 7.39 (t, J=1.8 Hz, 1H), δ 7.17 (d, J=8.1 Hz, 2H), δ 3.55 (q, J=8.7, 5.7 Hz, 2H), δ 3.45 (t, J=5.7 Hz, 2H), δ 2.60 (t, J=7.8 Hz, 2H), δ 1.56 (m, 2H), δ 1.30 (m, 2H), δ 0.90 (t, J=4.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.2, 131.7, 128.8, 127.4, 50.9, 39.7, 35.7, 33.5, 22.5, 14.1 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1481. found 246.1476.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](C4C=C5C(C=NN5C)=CC=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=O)C(C)(C)C.C(OC[C@@H](OC(C)(C)C)C1C(C)=CC2N=C([C:64]3[CH:65]=[C:66]4[C:70](=[CH:71][CH:72]=3)[N:69]([CH3:73])[N:68]=[CH:67]4)SC=2C=1C1C=CC(Cl)=CC=1)(=O)C(C)(C)C.CO.[OH-].[Na+]>C(OCC)(=O)C>[C:44]([O:43][C@@H:9]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:64]4[CH:65]=[C:66]5[C:70](=[CH:71][CH:72]=4)[N:69]([CH3:73])[N:68]=[CH:67]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[CH2:8][OH:7])([CH3:46])([CH3:47])[CH3:45]
Reactant: Cc1cc2nc(-c3ccc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 55 °C

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethyl pivalate and (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-indazol-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate was telescoped into the subsequent reaction. To the previous reaction mixture, methanol and 2M NaOH were added and reaction mixture was heated at 55° C. overnight. Reaction mixture was cooled to rt, diluted with ethyl acetate and washed with brine. The organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (Hex/EtOAc) to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([C:23]([OH:25])=[O:24])[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:33][Si](C=[N+]=[N-])(C)C>CO>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([C:23]([O:25][CH3:33])=[O:24])[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Solvent: CO
Product: COC(=O)c1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of 6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinecarboxylic acid (340 mg, 0.752 mmol) in methanol (20 mL) was added (trimethylsilyl)diazomethane (376 μL, 2.0 M in hexanes, 0.752 mmol). The reaction mixture was stirred at room temperature for 16 hours. Excess (trimethylsilyl)diazomethane was added and the reaction mixture was stirred 3 days. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (49-1 to 29-1 dichloromethane-methanol) provided methyl 6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)pyrimidine-4-carboxylate (45 mg, 13%). 1H NMR (CDCl3) δ 8.44 (d, 1H), 7.65 (m, 2H), 7.34 (t, 1H), 7.17 (t, 2H), 7.11 (d, 1H), 7.03 (s, 1H), 5.43 (br, 1H), 4.36 (m, 1H), 3.89 (s, 3H), 2.05 (m, 2H), 1.76–1.55 (m, 6H); MS m/z 466 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[NH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:36][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:35])[NH:26][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.3-5 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H): MS (ESI) min 494 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[C:12]1([CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:25](/[S:22]([NH:21][CH2:20][CH2:19][CH2:18][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:24])=[O:23])\[C:26]#[N:27])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C)c1O

Procedure:
M45 was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanomethylsulfonamide under similar conditions as described for M40 (part B).
Reaction SMILES: C(O)(=O)[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:10]1([CH:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: c1ccc(C(Nc2ccncc2)c2ccccc2)cc1
Temperature: 220 °C
Yield: 10.4 %

Procedure:
A mixture of 11.4 grams (0.05 mole) of benzilic acid and 4.7 grams (0.05 mole) of 4-aminopyridine was heated at 220° C. for 3.5 hours. After cooling the mixture was dissolved in toluene and washed with 10% sodium carbonate solution and with 2 N hydrochloric acid. The acidic extracts were basified with 5 N sodium hydroxide and the resulting oil extracted into toluene. After drying over magnesium sulphate, the toluene was removed and the yellow oil was recrystallised from light petroleum (b.p. 80°-100° C.) giving 1.35 grams (10% yield) of the title compound, m.p. 152° to 154° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (20.18 g), 4-benzyloxyphenol (17.70 g), anhydrous potassium carbonate (12.22 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (29.03 g, 88%) of 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole. Recrystallization from ethyl acetate-hexane gave colorless leaflet crystals. melting point: 126-127° C. A mixture of the obtained 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole (22.6 g), 5% palladium carbon (10.0 g) and tetrahydrofuran (300 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give crystals (16.3 g, 95%) of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>COC(C)(C)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-1-benzyl-3-pyrrolidinol (44.3 g, 0.25 mol) and 1,4-diazabicyclo[2.2.2]octane (33.7 g, 0.3 mol) in 250 mL of tert-butyl methyl ether under an atmosphere of nitrogen at 0° C., was added p-toluenesulfonyl chloride (52.4 g, 0.275 mol) portion-wise over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The ice bath was removed and the mixture was stirred at ambient temperature overnight (20±5 h). Ethyl acetate (100 mL) was added, followed by saturated aqueous sodium bicarbonate solution (250 mL). The resulting mixture was stirred at ambient temperature for 1 h. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (250 mL); saturated aqueous ammonium chloride solution (250 mL); saturated aqueous sodium chloride solution (250 mL); and then dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with ethyl acetate (20 mL) and the solvent was removed in vacuo to give 78.2 g of the title intermediate as an off-white solid (94% yield; 95% purity by HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1ccc(OC2CCN(c3ccccn3)CC2)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 2-[4-(4-chloromethylphenoxy)piperidine-1-yl]pyridine (404 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazol-4-yl]propionate (609 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:6]([S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:27].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>C1C=CC=CC=1>[C:34]1(=[O:43])[N:1]([CH2:2][C@H:3]2[C@H:6]([S:7][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:5][C:4]2=[O:27])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C1N[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Yield: 92.7 %

Procedure:
A solution of trans 3-aminomethyl-4-tritylthio-2-azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 ml) was heated under reflux for 15 h. The solvent was evaporated in vacuo and the residue crystallized from ether to give 17.4 g (93%) of the title compound; mp 172°-3° C.; Anal. calcd for C31H24N2O3S: C 73.78, H 4.79, N 5.55, found: C 73.92, H 4.87, N 5.49; ir (CHCl3) νmax : 1770 and 1715 cm-1 ; 1Hmr (CDCl3) δ: 7.8 (4H, m), 7.3 (15H, m), 4.45 (1H, d, J=2 Hz), 3.3-4.1 (3H, m) and 3.3-4.6 ppm (1H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=3[F:25])[N:3]=2)=[C:10]([F:17])[CH:11]=1
Reactant: Fc1cc(Br)cc(F)c1Cc1cccc(Br)n1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2cccc(Cc3c(F)cc(Br)cc3F)n2)c(F)c1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromo-6-(4-bromo-2,6-difluorobenzyl)pyridine (from Step C above, 7.41 g, 20.53 mmol) in toluene (200 mL) was added (2,4-difluorophenyl)boronic acid (3.89 g, 24.63 mmol), tetrakis(triphenylphosphine)palladium (2.37 g, 2.05 mmol), ethanol (20 mL) and 2M Na2CO3 (20 mL). The reaction was heated to 90° C. until complete. The mixture was cooled to room temperature and concentrated. The crude residue was diluted with EtOAc/water (1:1) and washed with 1N HCl (2×), brine (3×), dried over MgSO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (7.23 g).