Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[CH3:25]O>C(O)C>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH2:18][CH3:25])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[O:7]
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)C(=O)O)cc2)c1
Reactant: CO
Solvent: CCO
Product: CCC(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O

Procedure:
The mother liquor from the recrystallization of (−)20-cinchonidine salt was concentrated under reduced pressure. The enriched (+)20 isomer was obtained from the mother liquor by neutralizing the salt to obtain the free acid, as described previously for compound 18. The optical rotation showed that the isomer was approximately 80% enantiomeric excess, optical rotation was measured at 21° C.: [α]D+18.2° (c=1.2, methanol). A stock solution (1 mg/mL) of the racemic mixture (20) was prepared in ethanol/mobile phase (1:1). The injected sample volume was 250 μL. The compound was eluted with a mobile phase of heptane/ethanol. with 1% TFA (88:12) at a flow rate of 2.5 mL/min. Under these conditions, the (−)isomer eluted at 15.8 min and the (+)isomer eluted at 18.2 min retention times. The collected fractions were concentrated under reduced pressure at room temperature. (+)20 was collected as a white solid, 0.14 g. mp 146-148° C. The optical rotation was measured at 21° C.: [α]D+25.3° (c=0.5, methanol).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)(O)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C:15]([C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)=[CH:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCCC=C(c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of (R)-tert-butyl 2-((R)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholine-4-carboxylate (188 mg, 0.39 mmol) and Burgess' reagent (186 mg, 0.78 mmol) in toluene (3 mL) was heated to reflux under a N2 atmosphere for 2 h, then cooled to rt and diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography to give (S)-tert-butyl 2-(1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxypent-1-enyl)morpholine-4-carboxylate (133 mg, 73%). MS m/z 470 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1N=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[O:37]1C2C=CC(N3CCC(=O)CC3)=CC=2O[CH2:38]1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[O:2]1[C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=5)[CH2:16]4)[CH2:11][CH2:10]3)=[CH:7][C:38]=2[O:37][CH2:1]1
Reactant: O=C1CCN(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 1-(1,3-benzodioxol-5-yl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.79-1.85 (m, 2H), 2.03-2.18 (m, 3H), 2.40-2.47 (m, 1H), 2.67 (t, J=11.4 Hz, 2H), 3.13-3.21 (m, 1H), 3.35-3.43 (m, 2H), 3.54-3.64 (m, 4H), 4.03 (s, 2H), 4.48-4.50 (m, 1H), 5.86 (s, 2H) 6.42 (dd, J=8.4, 2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.69 (m, J=8.4 Hz, 2H), 7.70 (t, J=7.9 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.21 (s, 1H), 8.33 (s, 2H). MS m/z: 519 (M+1)
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(CO)ccc2c1
Product: COc1ccc2cc(CCl)ccc2c1

Procedure:
The 2-chloromethyl-6-methoxynaphthalene used as starting material is obtained from methyl 6-methoxy-2-naphthoate by reaction with sodium dihydro-bis-(2-methoxyethoxy)aluminate to give 2-hydroxymethyl-6-methoxynaphthalene, m.p. 118°-120° C. and reaction with thionyl chloride to give 2-chloromethyl-6-methoxynaphthalene, m.p. 63°-65° C. by the general procedure described in Example 4 for the preparation of 2-chloromethyl-6-chloronaphthalene.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[N:13]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2=[O:24])=[CH:7][CH:6]=1.[C:25](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[N:15]([CH3:25])[C:14](=[O:18])[N:13]([CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:12]2=[O:24])=[CH:9][CH:10]=1
Reactant: COc1ccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)C)c2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(-n2c(=O)n(C)c(=O)n(CC(C)(C)C)c2=O)cc1
Yield: 94.9 %

Procedure:
5.2 g (0.037 mol) of methyliodide are added dropwise to a solution of 10.0 g (0.033 mol) of 1-(4-methoxyphenyl)-3-(2,2-dimethylpropyl)-1,3,5-triazine-2,4,6-trione in 100 ml of absolute acetonitrile and 9 g (0.066 mol) of potassium carbonate at room temperature. The reaction mixture is boiled under reflux for 5 hours. After cooling the solid constituents are separated off and the mother liquor is concentrated under reduced pressure. The residue obtained after stripping off the solvent is ground with cold water for purification. The resulting crystals are filtered off with suction and dried. 10.0 g (95% of theory) of 1-(4-methoxyphenyl)-3-(2,2-dimethylpropyl)-5-methyl-1,3,5-triazine-2,4,6-trione are obtained in this manner in the form of crystals of melting point 134° C., IR:1685 cm-1. The substances listed by way of their formulae in the following Table 1 are also prepared by the method just described:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:14]([F:16])[F:15])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].C(N(CC)CC)C.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].[OH-].[Na+]>ClCCl>[F:15][CH:14]([F:16])[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCc1ccc(C(F)F)c(C(=O)O)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a mixture of methyl 5-(aminomethyl)-2-(difluoromethyl)benzoate hydrochloride (1.30 g, 5.17 mmol, 1.0 equiv) and triethylamine (1.51 mL, 10.85 mmol, 2.1 equiv) in dichloromethane (50 mL) at room temperature, add isobutyryl chloride (0.571 mL, 5.42 mmol, 1.05 equiv) and stir for one hour. Dilute the mixture with dichloromethane and wash with water then saturated aqueous NaCl. Separate the organic layer and dry over sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting crude material in 1,4-dioxane (10 mL), and add sodium hydroxide (5 N aqueous, 2 mL, 10 mmol, 1.93 equiv). Stir the resulting suspension at 40° C. overnight. Concentrate the mixture under reduced pressure, and treat the resulting residue with 1 N aqueous hydrochloric acid until the pH reaches 3. Extract the resulting suspension with EtOAc (2×30 mL). Wash the combined organic layers with saturated aqueous NaCl (50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound as a white solid (1.32 g, 94%). MS (m/z) 272 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([O:15][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
Sodium hydride (0.97 g, 24 mmol) was suspended in DMF (15 mL) under nitrogen at 0° C. A solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 8.7 mmol) in DMF (20 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 10 min and treated with a solution of methyl 4-(bromomethyl)benzoate (2.3 g, 10 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 1 h, and mixed with ethyl acetate and 1N HCl solution. The EtOAc layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.2 g, 37%). 1H NMR (CDCl3) δ 7.99 (d, J=8.1 Hz, 2H), 7.36 (d, J=3.5 Hz, 2H), 4.78-4.26 (m, 3H), 4.19-4.11 (m, 1H), 3.90 (s, 3H), 3.71-3.46 (m, 2H), 2.84-2.39 (m, 1H), 2.23-2.04 (m, 1H), 1.48 (br. s., 9H); MS(ESI+) m/z 324.0 (M-55)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH2:19]([OH:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:21][CH2:19][CH3:20])[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: CCO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccc(C)o2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, ethanol and DBU in DME. ES-MS m/e (%): 245 (M+H+, 100), 217 ([M+H—CH2═CH2]+, 80).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[C:10]([F:14])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[C:10]([F:14])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1c(F)cccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(F)cccc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
5′-Amino-3,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 mL), 48% aqueous hydrobromic acid (40 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 mL) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 mL) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography on silica gel eluting with isohexane (containing 0.5% methanol) on a gradient of ethyl acetate (2-6%) gave 5′-bromo-3,2′-difluoro-biphenyl-2-carbonitrile (2.48 g, 68%) as a yellow solid: δH (400 MHz, CDCl3) 7.13 (1H, dd, J 9 and 9), 7.27-7.30 (2H, m), 7.53-7.59 (2H, m), 7.64-7.69 (1H, m).
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([CH2:9]O)[CH2:8][CH2:7]1.[Br-].[Li+].[O:13]1[C@@H:25]2[C@@:26]34[CH2:28][CH2:29][NH:30][C@@H:20]([C@:21]3([OH:32])[CH2:22][CH2:23][C:24]2=[O:31])[CH2:19][C:18]2=[C:27]4[C:14]1=[C:15]([OH:33])[CH:16]=[CH:17]2>CN(C=O)C.C(N(CC)CC)C>[CH2:7]1[CH:6]([CH2:9][N:30]2[C@@H:20]3[CH2:19][C:18]4[CH:17]=[CH:16][C:15]([OH:33])=[C:14]5[O:13][CH:25]6[C:24]([CH2:23][CH2:22][C@:21]3([OH:32])[C@:26]6([C:27]=45)[CH2:28][CH2:29]2)=[O:31])[CH2:8]1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3)[C@H]1O5
Reactant: OCC1CC1
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Temperature: 2.5 °C

Procedure:
Methanesulphonyl chloride (76 kg) was added to the mixture of cyclopropyl methanol (50 kg) and triethylamine (192 L) in DMF (400 L) maintained at 0-5° C., the reaction mixture was maintained at 0-5° C. for 3.0 hrs. Lithium bromide (60 Kg) was added to reaction mixture at 0-15° C. and maintained for 10-15 minutes. Noroxymorphone (40 Kg) was added to above reaction mixture at 0-5° C. and temperature raised to 65-70° C. over 1.0 hr period and maintained for 14-15 hrs. After completion of reaction it was quenched in ice-water below 20° C. and the product was extracted with ethylacetate. The ethylacetate layer was concentrated and the product was isolated with MDC and cyclohexane mixture at 10-15° C. Yield=35.3 Kg.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:12]([S:5][CH2:4][CH2:3][NH2:2])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
2-Aminoethanethiol hydrochloride (1.0 g, 8.6 mmol) was dissolved in acetic trifluoride (10 ml) and added with triphenylmethanol (2.32 g, 8.6 mmol). The resulting solution was stirred at room temperature for 1 hr and concentrated by distilling under reduced pressure. The filtrate was diluted with ethyl acetate (50 ml) and washed with 3 M sodium hydroxide aqueous solution, water, saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a white solid of 2-(tritylsulfanyl)-1-ethaneamine (2.32 g, 7.3 mmol, 85.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)[C:30]=3[C:22]=2[CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=4)[C:30]=3[C:22]=2[CH:21]=1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Cl)c(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(S(C)(=O)=O)cc3)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a mixture of 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid (0.9 g, 0.0035 mol), the title compound of Example 92 (0.0024 mol) and 1 mL of diisopropylethylamine in 25 mL of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 h. Solvent was removed and the residue was purified on preparative HPLC to give the product as a pale white solid (89% yield); mp: 194-195° C.; 1HNMR (DMSO+TFA-d, 400 MHz) δ: 10.29 (s, 1H), 8.10 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 7.43 (dd, J=2.1, 8.2 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J=2.0, 8.2 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.08 (dd, J=3.0, 8.9 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 3.89 (d, J=12.8 Hz, 2H), 3.51 (d, J=12.8 Hz, 2H), 3.23(s, 3H), 3.11 (m, 2H), 2.95 (m, 4H), 2.86 (m, 2H). The bioactivity in the IKK 2 Resin assay for the compound of Example 126 is shown in Table 2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2].[Na+].[C:17]([O:23][CH2:24]Br)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)P(N(C)C)(N(C)C)=O.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH2:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O:15][CH2:24][O:23][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=C(C(=O)[O-])N2C(=O)CC2C1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (23 mg) and bromomethyl pivalate (29 mg) in hexamethylphosphoramide (0.5 ml) is stirred at room temperature and under a N2 atmosphere for 2.5 hrs. The mixture is diluted with toluene (10 ml), washed with H2O (5×2 ml) and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residue is purified by silica gel plc to afford pivaloyloxymethyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[N:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1n[nH]c2cc(OC)c(OC)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 6,7-dimethoxy-4-oxo-1,4-dihydrocinnoline-3-carboxylate (1.00 g, 3.6 mmol) (Method 5) was added phosphorous oxychloride (15 mL). The reaction flask was fitted with a reflux condenser and heated to reflux for 2 h before being allowed to cool to rt. The crude reaction mixture was concentrated in vacuo, and the residue was treated with aqueous NaHCO3 (˜25 mL). The crude product precipitated from solution and was collected via vacuum filtration using a Buchner funnel. The solid was washed water (1×100 mL) and diethyl ether (1×100 mL) to yield 0.941 g (88%) of the title compound as a light brown solid that was used without further purification. 1H NMR: 7.98 (s, 1H), 7.50 (s, 1H), 4.55 (q, 2H), 4.13 (s, 6H), 1.45 (t, 3H); m/z 298.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]([NH2:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[OH-]>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:18][C:11]([CH3:17])([CH3:10])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
Example 1(b) was repeated, except that the amounts of cyanuric chloride, mixed xylene, 1,1,3,3-tetramethylbutylamine and 20% aqueous hydroxide solution were changed to 53.0 grams (0.287 mole), 132 grams, 38.0 grams (0.294 mole) and 58.8 grams, respectively, to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([C@H:11]1[NH:14][C:13](=[O:15])[CH2:12]1)#[CH:10]>ClCCl.C(N(C(C)C)C(C)C)C>[Si:1]([N:14]1[C@H:11]([C:9]#[CH:10])[CH2:12][C:13]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[C@@H]1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
tert-butyldimethylsilyl chloride (1.42 g) was added to a mixture of 4(S)-ethynyl-2-azetidinone (0.78 g) in dichloromethane (10 ml) and ethyldiisopropylamine (2.14 ml) at room temperature. The reaction mixture was stirred overnight, then evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with n-hexane-ethyl acetate (9:1) to give 1-tert-butyldimethylsilyl-4(S)-ethynyl-2-azetidinone (1.4 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cc(-c2ccccc2)c2ccccc21
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
In 400 ml of tetrahydrofuran, 42.0 g of 3-phenyl indole was solved. The solution and 25.0 g of potassium tert-butoxide added thereto at -30--20° C. were together heated to normal room temperature and stirred for 30 minutes. The reaction solution was cooled to -20--10° C. and 26 ml of benzoyl chloride added thereto were together heated to normal room temperature and stirred for one hour. The resultant mixture was poured into ice water and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, distilled to expel the chloroform, crystallized by addition of isopropyl ether, separated by filtration, and dried to obtain 60.0 g of 1-benzoyl-3-phenylindole (92.8%) having a melting point of 154-156° C.