Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[OH:1][C:2]1[CH:10]=[C:9]([NH:11][C:14](=[O:16])[CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(C(=O)[O-])c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 100 °C
Yield: 56 %

Procedure:
Sodium 2-hydroxy-4-aminobenzoate (76 g, 0.437 mole) was dissolved in water (2-300 ml) and concentrated hydrochloric acid (36.2 ml) was added after which the precipitated crystalline free acid was isolated by filtration. The acid was suspended in water (700 ml), acetic anhydride (48 ml) was added and the mixture was heated to about 100° C. (supplied with a reflux condenser) for 15 minutes under nitrogen. After cooling, the crystalline material was filtered off and dried in vacuo to give the title compound (48 g, 56%), m.p. 221°-223° C. Found (Calc. for C9H9NO4) C 55.14 (55.38), H 4.73 (4.62), N 7.12 (7.18).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20].[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)(Cl)Cl>[OH:17][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([S:23]([Cl:22])(=[O:25])=[O:24])[C:9]=2[CH3:16])[CH2:7][C:2](=[O:1])[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(=O)(=O)Cl)c2C)CC1=O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (1.8 g) in chloroform (20 ml) was stirred and cooled to 0° C. during the dropwise addition of chlorosulphonic acid (10 ml). The mixture was stirred for four hours at 20° C. and then poured into ice-water and the aqueous phase was extracted with chloroform (50 ml). The organic phase was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product 3-hydroxy-5-(2,4,6-trimethyl-3-chlorosulphonylphenyl)-2-propionylcyclohex-2-en-1-one was isolated as a brown oil (2.4 g, 97%). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.16 (3H, t); 2.47 (3H, s); 2.69 (3H, s); 2.80 (3H, s); 2.7-4.0 (7H, m); 7.05 (1H, s); 18.30 (1H, s).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH:20]2[CH2:23][NH:22][CH2:21]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH:32]1[CH2:34][O:33]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C.O>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH:32]([OH:33])[CH2:34][N:22]1[CH2:23][CH:20]([CH2:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:21]1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: Fc1ccc(C2CO2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(CC1CN(CC(O)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Triethylamine (210 μL, 1.52 mmol) was added to a stirred suspension of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4, 270 mg, 1.02 mmol) in acetonitrile (3 mL) under nitrogen. 2-(2,4-Difluorophenyl)oxirane (WO 99/23083; 1:1 mixture of enantiomers, 238 mg, 1.52 mmol) was added followed by lithium perchlorate (110 mg, 1.03 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane (x3). The combined organic layers were washed with water (x3) and brine, dried over MgSO4 and evaporated in vacuo. The residue was triturated with diethyl ether/isohexane then with 5% methanol/ethyl acetate to give 1-(2,4-difluorophenyl)-2-(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)ethanol (134 mg, 34%). 1H NMR (500 MHz, CD3OD) δ 7.96–7.92 (2H, m), 7.50–7.46 (1H, m), 7.39–7.33 (2H, m), 6.93–6.91 (1H, m), 6.88–6.84 (1H, m), 3.48 (2H, d, J=7.3 Hz), 3.44–3.38 (2H, m), 2.96–2.88 (2H, m), 2.83–2.75 (1H, m), 2.67–2.61 (2H, m); m/z (ES+) 386 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:22]([O-])(=O)C.[Na+].C=O>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:2]2[NH:1][C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH2:20][CH2:21]1
Reactant: CC(=O)[O-]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: c1cnc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Product: c1ccc(N2CCN(Cc3cc4cccnc4[nH]3)CC2)nc1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 1-(2-pyridinyl)piperazine (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.49 (m, 4H) 3.45 (m, 4H) 3.67 (s, 2H) 5.59 (s, 1H) 6.60 (dd, J=6.78, 5.09 Hz, 1H) 6.77 (d, J=8.82 Hz, 1H) 7.04 (dd, J=7.97, 4.58 Hz, 1H) 7.49 (m, 2H) 8.06 (m, 1H) 8.19 (dd, J=4.75, 1.70 Hz, 1H) (ESI) 294 m/z (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>CCOCC>[OH:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)C1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40 mmol) in ether (20 ml) was added dropwise phenylmagnesium bromide (10.3 mL, 3.0 M in ether, 6.21 mmol) at rt under nitrogen. The reaction was heated to reflux for 15 min, then cooled to rt, poured into sat. NH4Cl, extracted with ether (3×). The combined organic layers were dried over Na2SO4, concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (700 mg, 49.24%). LCMS (M+H) 264.160.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2[nH]c3ccccc3c2C[C@H]2CCCCN2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCC[C@@H]1Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
To a solution of 1.1 g (3.8 mmol) of 2-phenyl-3-(piperidin-2(R)-ylmethyl)-1H-indole and 238 mg (3.8 mmol) of sodium cyanoborohydride in methanol (20 ml) at 0° C. was added a solution of formaldehyde (527 mg of a 37% w/w aqueous solution) and glacial acetic acid (0.5 ml, 8.7 mmol) in methanol (10 ml). After stirring at room temperature for 3 hr the reaction was evaporated in vacuo. The residue was partitioned between saturated potassium carbonate (20 ml) and EtOAc (20 ml), the organic layer separated, and the aqueous layer extracted with EtOAc (2×20 ml). The combined EtOAc layers were washed with water (50 ml), saturated sodium chloride (50 ml), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (SiO2; 5% MeOH in CH2Cl2+0.5% NH3) and the product recrystallised from Et2O/hexanes to afford 210 mg (0.7 mmol; 18%) of 3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole as a white solid. (Found: C, 81.50; H, 7.98; N, 9.14; C21H24N2.0.25H2O requires C, 81.64; H, 7.99; N, 9.07%); mp 150° C. (from Et2O/hexane); [α]D23+80.0 (c 1.0 in CHCl3); δH (360 MHz; CDCl3) 0.96-1.14 (2H, m, aliphatics), 1.44-1.58 (4H, m, aliphatics), 2.06-2.16 (1H, m, aliphatic), 2.21-2.32 (1H, m, aliphatic), 2.46 (3H, s, CH3), 2.76-2.89 (2H, m, aliphatics), 3.47 (1H, dd, J 13.8 and 3.8, indole CHAHB), 7.14 (1H, m, indole H5), 7.20 (1H, m, indole H6), 7.33-7.38 (2H, m, aromatics), 7.43-7.47 (2H, m, aromatics), 7.57 (2H, d, J 7.1, aromatics), 7.65 (1H, d, J 7.8, aromatic), 8.05 (1H, br s, NH); m/z (ES+) 305 (M++H, 100%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:10]([CH3:11])[C:9]([C:8]1[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=[N:6][CH:7]=1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cncnc1CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ncncc1C(=O)C(C)Br
Yield: 88.2 %

Procedure:
49.2 g (0.30 mol) of 1-(4-ethylpyrimidin-5-yl)propan-1-one was dissolved in 500 ml of carbon tetrachloride, and 53 g (0.30 mol) of N-bromosuccinimide and 0.3 g of azoisobutyronitrile were added, followed by refluxing for 2 hours. After cooling, crystals were removed by filtration, and the filtrate was concentrated and the obtained oily product was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 1:2) to obtain 64.3 g (yield: 89%) of 2-bromo-1-(4-ethylpyrimidin-5-yl)-propan-1-one as yellow liquid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[CH3:49]>CN(C=O)C.O>[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:15])[CH3:49]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a stirred solution of 5-phenyl-pyridine-2-carboxylic acid (0.3 g, 0.00151 mol) in DMF (5 mL) was added DIPEA (0.580 g, 0.00452 mol), HOBt (0.243 g, 0.00180 7 mol) and EDCI.HCl (0.346 g, 0.001807 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.252 g, 0.00181 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.32 g (75%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00113 mol) in a mixture of THF (3.2 mL), methanol (2 mL) and H2O (1 mL) was added LiOH.H2O (0.142 g, 0.00338 mol) and the resulting mixture was stirred at ambient temperature overnight. Volatiles were removed by evaporation and the resulting residue was diluted with water and acidified with 10% HCl. The product was extracted with ethyl acetate, which was dried over sodium sulfate and concentrated under reduced pressure to afford 0.24 g (83%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25]/[C:26](=[CH:32]\[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([NH:45][CH3:46])[N:40]=2)=[CH:35][CH:34]=1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25]/[C:26](=[CH:32]\[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([N:45]([CH3:46])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[N:40]=2)=[CH:35][CH:34]=1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)n2)cc1)OCC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.6 %

Procedure:
0.55 g (2.75 mmol) of 4-nitrophenyl chloroformate and then 0.48 mL (2.75 mmol) of diisopropylethylamine are added to a solution of 0.6 g (1.84 mmol) of ethyl (Z)-2-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]acrylate in 15 mL of dichloromethane. The reaction mixture is stirred for 1 hour 30 minutes at room temperature. The reaction is worked up by addition of 10 mL of water and extraction with dichloromethane. The organic phases are combined and then dried over magnesium sulfate, filtered and the solvent is evaporated off. 1 g (100%) of ethyl (Z)-2-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)acrylate is obtained in the form of a yellow oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][N:4]1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:3]3=[O:2])[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C(N[C@H]1CCCN(C2CCNCC2)C1=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
A flask was charged with (S)-benzyl 2-oxo-1,4′-bipiperidin-3-ylcarbamate hydrochloride (4.1 g, 11 mmol), 2-chloro-5-ethylpyrimidine (1.7 g, 12 mmol), DIEA (3.9 mL, 22 mmol), and DMF (30 mL). The reaction was heated to 100° C. overnight. The reaction was cooled to ambient temperature, concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-ylcarbamate (2.8 g, 57% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[CH:5]([OH:7])O.[C:10]1([CH:16]=[CH:17][CH2:18]Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH2:20]>CN(C=O)C>[CH3:3][C:4]([CH3:9])([CH2:5][O:7][CH2:18][CH:17]=[CH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][OH:20]
Reactant: ClCC=Cc1ccccc1
Reactant: O
Reactant: CC(C)(C)C(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CO)COCC=Cc1ccccc1
Temperature: 0 °C

Procedure:
In a dry three-neck flask under an atmosphere of N2 was placed 14.4 g (0.6 mole) of NaH and 100 ml of DMF. The mixture was stirred and a solution of 52.1 g (0.5 mole) of 2,2-dimethylpropandiol in 75 ml of DMF was added dropwise. Stirring was continued until the gas evolution ceased, then a solution of 91.57 g (0.6 mole) of 3-phenyl-2-propenyl chloride in 50 ml of DMF was added. The reaction mixture was stirred at room temperature for two days, then poured into 500 ml of ice and water. The aqueous solution was extracted with three 300 ml portions of ethyl ether. The organic layers were combined and washed with H2O, saturated NaCl solution, and then dried over MgSO4. The solvent was removed on a rotary evaporator to give a brick red liquid. Kugelrohr distillation gave the title compound, bp 100°-110°/0.025-0.005 mm Hg. The product was a mixture of cis and trans isomers.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H:33]2[NH:37][C:36](=[O:38])[N:35]([C@H:39]([C:48]3[NH:49]C(C4C=CC(I)=CC=4F)=C(C)[N:52]=3)[C@H:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:41])[C:34]2=[O:62])CC1.[Br:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=O)[CH2:71][CH3:72])=[CH:66][CH:65]=1.C(OC(N[C@H]([C:86]1[CH:91]=[CH:90][C:89]([O:92][CH2:93][C:94](=[O:98])N(C)C)=[CH:88][CH:87]=1)C(O)=O)=O)(C)(C)C.ClN1C(=O)CCC1=O>>[Br:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[NH:49][C:48]([C@@H:39]([N:35]3[C:34](=[O:62])[C@@H:33]([C:86]4[CH:91]=[CH:90][C:89]([O:92][CH2:93][CH2:94][OH:98])=[CH:88][CH:87]=4)[NH:37][C:36]3=[O:38])[C@H:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH3:41])=[N:52][C:71]=2[CH3:72])=[CH:66][CH:65]=1
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(Br)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) commercially available 1-(4-bromo-phenyl)-propan-1-one was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 106-D and (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 106-F was omitted. HR-MS: calcd for C30H29BrN4O4 [M+H+] 589.1445. Found 589.1444.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[O:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)Cl>[C:9]([O:8][C:6]([NH:1][CH2:2][CH2:3][NH2:4])=[O:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN
Reaction time: 20 h

Procedure:
To a stirred solution of 1,2-diaminoethane 2-3 (50 g, 832 mmol) and CH2Cl2 (500 ml) was added a solution of BOC2O (45 g, 208 mmole) in CH2Cl2 (100 ml) dropwise over a 3 h period. After 20 h, the reaction was filtered and then the filtrate was concentrated at 60° C. to furnish amine 2-4 as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>CC#N>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][O:5][N:6]2[C:15](=[O:16])[CH2:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]2=[O:17])[CH2:31][CH2:32]1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1OCCCN1CCN(c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (5.0 g) and 1-(2-benzothiazolyl)piperazine (3.6 g) in 100 ml of anhydrous CH3CN was added diisopropylethylamine (5.7 ml). The mixture was stirred at room temperature for 18 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@@H:5]([CH2:26][CH:27]=C)[C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][C:9]1=[O:25])=[O:7].[O:34]=O.N#N.S(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]([C:6](=[O:7])[N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][C:9]1=[O:25])[CH2:26][CH:27]=[O:34]
Reactant: O=O
Reactant: C=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: N#N
Solvent: CSC
Solvent: ClCCl
Product: O=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Dissolve (4S,5R)-3-((R)-2-(2-chloro-6-fluorobenzyl)pent-4-enoyl)-4,5-diphenyloxazolidin-2-one (1.05 g, 2.27 mmol) in CH2Cl2 (200 mL). Cool the solution to −78° C. Bubble O2 into the solution until the solution turns blue. Then bubble N2 for 5 minutes and add Me2S (0.706 g, 11.3 mmol). Stir the mixture for one hour and then remove the solvent. Purify the residue by chromatography (Silica gel) to afford (S)-3-(2-Chloro-6-fluorobenzyl)-4-oxo-4-((4S ,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl)butanal (0.384 g, 36%). 1H NMR (CDCl3) δ 7.18 (m, 2H), 7.12 (m, 6H), 6.98 (m, 3H), 6.82 (m, 2H), 6.00 (d, 1H), 5.69 (d, 1H), 4.72 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.92 (m, 1H), 2.61 (m, 1H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17](C)C(O)=O>>[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH3:17])[C:10]1=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCCN1C(=O)c1ccccc1
Reactant: CC(Cl)C(=O)O
Product: CC1OCCN(C(=O)c2ccccc2)C1=O

Procedure:
Synthesized as for N-benzoyl-3-oxomorpholine (Example I) using 2-chloropropionic acid (Aldrich) in place of chloroacetic acid.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(N(CC)CC)C>[C:22]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)N1CC(c2ccccc2)c2ccccc21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture comprising 4.0 g of 3-phenylindoline, 40 ml of benzene, 5 ml of triethylamine and 4.0 g of acryloylchloride was stirred at 10°-15° C for 15 minutes. The mixture was then washed with water, the benzene solution dried and the solvent removed. 4.1 G of resin which was crystallized from ether to give 2.3 g of the desired N-acryloyl-3-phenylindoline which was found to have a melting point of 77°-8° C.
Reaction SMILES: C([Li])CCC.C(O)(C)(C)C.[CH2:11]([O:13][C:14]([NH:16][C:17]1[CH:37]=[CH:36][C:20]([C:21]([C:23]2[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=2)=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH3:12].[CH3:38][OH:39]>C1COCC1>[OH:39][CH2:38][C@@H:11]1[O:13][C:14](=[O:15])[N:16]([C:17]2[CH:37]=[CH:36][C:20]([C:21]([C:23]3[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=3)=[O:22])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CCOC(=O)Nc1ccc(C(=O)c2cccn2COCC[Si](C)(C)C)cc1
Reactant: CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc(N2C[C@H](CO)OC2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (4.6 ml. of 1.6 M solution in THF, 7.36 mM) was added to a stirred solution of t-butanol (0.505 g) in dry THF at −20° C. under nitrogen and the mixture stirred for 20 minutes. The temperature was lowered to −60° C. and 2-(4-ethoxycarbonylaminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole (2.2 g. 5.67 mM) added over 15 minutes. The mixture was stirred for 50 minutes and a solution of R-(−) glycidyl butyrate (0.9 g. 6.25 mM) in dry THF (5 ml) added. The mixture was allowed to warm to ambient temperature and stirred for 24 hours. MeOH (20 ml) was added and the solution evaporated and the residue partitioned between EtOAc and water The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using 2% MeOH/dichloromethane as eluant, to give 5(R)-hydroxymethyl-N-(4-[1-(2-trimethylsilylethoxymethyl)pyrrol-2-ylcarbonyl]phenyl)oxazolidin-2-one as an oil (0.77 g; MS: 417 (MM−)).
Reaction SMILES: [OH2:1].[OH-].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11])([O-:6])=[O:5].C(Cl)Cl>C1COCC1>[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:1])=[O:11])([O-:6])=[O:5]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Reaction time: 174 h

Procedure:
1 liter water and 60 g NaOH are added to 100 g Vulkadur RB® and a solution of 200 g 3-nitrobenzoyl chloride in 300 ml THF is then added with stirring (cooling with ice). After 174 h, 500 ml CH2Cl2 are added and the organic phase is separated off and concentrated by evaporation. The N content of the product corresponds to the theoretical.