Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:49][NH:50][O:51][CH3:52]>C(OCC)(=O)C.CN(C)C=O>[CH3:52][O:51][N:50]([CH3:49])[C:12]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:16][CH2:15]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of N-tert-butoxycarbonyl isonipecotic acid (1.50 g, 6.54 mmol, 1 eq), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.88 g, 9.81 mmol, 1.5 eq), 1-hydroxybenzotriazole (1.33 g, 9.81 mmol, 1.5 eq), and N,N-dimethylformamide (26 ml) was treated with N,N-diisopropylethylamine (4.60 ml, 26.2 mmol, 4 eq). The resultant yellow solution was stirred at room temperature for 5 minutes, and then N,O-dimethylhydroxylamine hydrochloride (766 mg, 7.85 mmol, 1.2 eq) was added, and stirring continued for 92 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed sequentially with 1 N aq. NaOH, 1 N aq. HCl and brine. The organic phase was dried over Na2SO4 and concentrated to give an oil which was used with no further purification.
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(NCC1C=CC=C(NC(=O)CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)C=1)=O)NC2=O)#N.[C:53]([C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[N:61]=[C:60]([C:65]([NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([NH:75][C:76]([C:78]3[N:82]=[CH:81][N:80](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:79]=3)=[O:77])[CH:70]=1)=[O:66])[NH:59][C:58]2=[O:102])#[N:54]>>[C:53]([C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[N:61]=[C:60]([C:65]([NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([NH:75][C:76]([C:78]3[N:82]=[CH:81][NH:80][N:79]=3)=[O:77])[CH:70]=1)=[O:66])[NH:59][C:58]2=[O:102])#[N:54]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Agent: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)c4nc[nH]n4)c3)[nH]c(=O)c2c1

Procedure:
By a method similar to that in Step 2 of Example 32 and using, instead of 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide, 6-cyano-4-oxo-N-{[3-({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide, the title compound was obtained as a white powder (355 mg, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[OH-].[Na+:23]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[S:18][C:17]([C:19]([O-:21])=[O:20])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[Na+:23]
Reactant: CC(C)CSc1ccc(-c2ccc(C(=O)O)s2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CSc1ccc(-c2ccc(C(=O)[O-])s2)cc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using [3-cyano-4-(isobutylthio)phenyl]boronic acid and methyl 5-bromothiophene-2-carboxylate, 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylic acid was obtained in accordance with the method of Example 2. Then, 333 mg of the resulting 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylic acid was suspended into 10 ml of ethanol, and 1.05 ml of a 1 M aqueous sodium hydroxide solution was added to the suspension, followed by stirring at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, the residue was suspended into 2-propanol, and the precipitate was collected by filtration to obtain 256 mg of sodium 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylate.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([S:39][CH3:40])=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([S:39][CH3:40])=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(SC)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(SC)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 25 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 5-ethynyl-1-methyl-2-methylsulfanyl-1H-imidazole in the same manner as Example 15. ESI MS m/z 584 [C27H33N7O4S+H]+.
Reaction SMILES: C(OC(N1C(C2NC(C3C=CC4C5C=CC(Br)=CC=5OC=4C=3)=CN=2)CC2(CC2)C1)=O)C1C=CC=CC=1.[C:37]([O:41][C:42]([N:44]1[CH:49](C2NC3C=C(B4OC(C)(C)C(C)(C)O4)C=CC=3N=2)[CH:48]2[CH2:68][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH:48]2[CH2:68][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)oc2cc(Br)ccc23)[nH]1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC2CCC1C2
Yield: 267.5 %

Procedure:
To the solution of 6-[5-(7-bromo-dibenzofuran-3-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (150 mg, 0.28 mmol) and 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (78 mg, 0.56 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 90 C for 16 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 34647-[2-(5-benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-dibenzofuran-3-yl]-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (190 mg). m/z: 775.2 (M+1), 773.3 (M−1), 338.2 (M+2)/2.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]1[CH2:37][O:36][C:10]2([CH2:32][CH2:31][C@@:30]3([CH3:33])[C:12](=[CH:13][CH2:14][C@@H:15]4[C@:29]3([OH:34])[CH2:28][CH2:27][C@@:26]3([CH3:35])[C@H:16]4[CH2:17][CH:18]=[C:19]3[CH:20]([N+:23]([O-:25])=[O:24])[CH2:21][OH:22])[CH2:11]2)[O:9]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:22][CH2:21][CH:20]([N+:23]([O-:25])=[O:24])[C:19]1[C@:26]2([CH3:35])[C@H:16]([C@H:15]3[C@:29]([OH:34])([CH2:28][CH2:27]2)[C@:30]2([CH3:33])[C:12]([CH2:11][C:10]4([O:9][CH2:8][CH2:37][O:36]4)[CH2:32][CH2:31]2)=[CH:13][CH2:14]3)[CH2:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CC=C(C(CO)[N+](=O)[O-])[C@@]4(C)CC[C@@]12O)OCCO3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C1=CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Acetic anhydride (1.5 ml) was added to a stirred suspension of 3,3-ethylenedioxy-20-nitropregna-5,16-diene-9α,21-diol (1.00 g of diastereomer II, prepared according to example 2), and 4-dimethylaminopyridine (100 mg) in methylene chloride (10 ml) to give a clear solution. The reaction mixture was stirred for an additional 30 minutes and concentrated under reduced pressure. The residue was dissolved in methylene chloride and filtered over a silica gel column. The filtrate was evaporated under reduced pressure to afford a white solid which was dried under reduced pressure at 50° C.
Reaction SMILES: CO.[O:3]1[CH2:5][C@H:4]1[CH2:6][N:7]([CH2:17][C@@H:18]1[CH2:20][O:19]1)[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClC1C=CC=CC=1>[CH2:21]([N:28]1[CH2:5][C@H:4]([OH:3])[CH2:6][N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:17][C@@H:18]([OH:19])[CH2:20]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(C[C@@H]1CO1)C[C@@H]1CO1
Solvent: CO
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccccc1)N1C[C@@H](O)CN(Cc2ccccc2)C[C@H](O)C1
Temperature: 65 °C

Procedure:
Methanol (2494 kg, 18 rel. vol.—either fresh or recycled) was charged to a reaction vessel and heated to reflux temperature (approx. 65° C.). Simultaneously, and over approximately 6 hours were charged the chlorobenzene solution (containing chirally enriched N,N-bis(2(R)-oxiranylmethyl)benzenesulfonamide) from step (i), Alternative 2 above and benzylamine (109 kg, 0.91 eq.). The batch was maintained at reflux throughout the addition. The reaction was stirred at approximately 65° C. (reflux temperature) for a further 3 hours. Methanol (1938 kg, 14 rel. vol.) was then removed by distillation at atmospheric pressure before chlorobenzene (775 kg, 4 rel. vol.) was added. The resulting solution was used without further treatment in the next step (see step (iii), Alternative 2 below).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.BrC1C=C(C(Cl)=O)C(Br)=CC=1C(Cl)=O.[O:29]1[CH2:34][CH2:33][NH:32][C:31]2[CH:35]=[N:36][CH:37]=[CH:38][C:30]1=2>CN(C)C=O.S(Cl)(Cl)=O.ClCCl.C(N(CC)CC)C>[Br:14][C:8]1[CH:7]=[C:3]([C:4]([N:32]2[CH2:33][CH2:34][O:29][C:30]3[CH:38]=[CH:37][N:36]=[CH:35][C:31]2=3)=[O:6])[C:2]([Br:1])=[CH:10][C:9]=1[C:11]([OH:13])=[O:12]
Reactant: c1cc2c(cn1)NCCO2
Reactant: O=C(O)c1cc(Br)c(C(=O)O)cc1Br
Agent: O=C(Cl)c1cc(Br)c(C(=O)Cl)cc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(Br)c(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 20 ml flask, 2,5-dibromo-terephthalic acid (100 mg, 0.31 mmol) and N,N-dimethyl formamide (3 drops) were dissolved in thionyl chloride (2 ml). After stirring for 2 hours at 800, the reaction mixture was cooled to room temperature and concentrated. Crude 2,5-dibromo-terephthaloic dichloride (112 mg, 0.31 mmol) was dissolved in dichloromethane (6 ml) and was added to 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (20.9 mg, 0.15 mmol) dissolved in dichloromethane (1 ml). Triethylamine (3 drops) were slowly added thereto and stirred at room temperature for 16 hours. After completion of the reaction, the residue was purified by preparative LC/Mass to obtain the target compound 23, i.e., 2,5-dibromo-4-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-carbonyl)-benzoic acid, as white solid (23 mg, 5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>C1COCC1.C(Cl)Cl>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:11][CH2:10]2)[CH:17]=[CH:16][CH:15]=1)(=[O:23])[CH:20]([CH3:21])[CH3:22]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-dimethoxybenzoyl chloride: ESMS m/e: 482.0 (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[N:9]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:25]4[CH2:26][C:27]5[S:28][CH:29]=[CH:30][C:31]=5[C:24]=4[N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:22]=3)=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(Cl)Cl>[Br:8][C:29]1[S:28][C:27]2[CH2:26][C:25]3[C:21]([C:18]4[CH:17]=[CH:16][C:15]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[CH:20][CH:19]=4)=[N:22][N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:24]=3[C:31]=2[CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1ccsc1C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1cc(Br)sc1C2
Reaction time: 2 h
Yield: 80 %

Procedure:
NBS (0.18 g, 1.0 mmol) was added to a solution of 6-(4-Morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.23 g, 0.5 mmol) in CH2Cl2 (5.0 mL). After 2 hr, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 2-Bromo-6-(4-morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.21 g, 0.4 mmol) as brown solid in 80% yield.
Reaction SMILES: [C:1]1([CH:7]2[CH2:22][C:15]3([C:19](=[O:20])[NH:18][C:17](=O)[NH:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[C:1]1([CH:7]2[CH2:22][C:15]3([C:19](=[O:20])[NH:18][C:17](=[S:32])[NH:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Oc3ccccc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccccc12
Yield: 47.4 %

Procedure:
A suspension of 2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 2.04 mmol) and Lawesson's Reagent (825 mg, 2.04 mmol) in dry 1,4-dioxane (28 mL) is heated under reflux for 24 h. The mixture is concentrated in vacuo and the residue is purified by column to give 2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (300 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:17](=[O:34])[CH2:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[C@H:24]([O:26][Si](C(C)(C)C)(C)C)[CH3:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]=[C:14]([C:17](=[O:34])[CH2:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[C@H:24]([OH:26])[CH3:25])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a solution of (3S,4R)-4-[2-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (4.65 g) in acetonitrile (25 ml) was added dropwise boron trifluoride ether complex (2.6 ml) at 0° C., and the mixture was stirred for 1 hour. Sodium hydrogen carbonate (5 g) was added to the reaction mixture, followed by stirring for 30 minutes, and then precipitate was filtered off. Filtrate was dissolved in ethyl acetate (100 ml), washed in turn with water (50 ml) and brine (50 ml), dried over magnesium sulfate. Evaporation of the solvent in vacuo gave (3S,4R)-4-[2-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl]-3-[(1R)-1-hydroxyethyl]-2-oxoazetidine (3.6 g).
Reaction SMILES: C[CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4](C)C.CNC.BrC[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=C[C:16]=1[F:24].CCOC(C)=O>C1COCC1>[F:24][C:16]1[CH:15]=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:9]=1[CH2:7][N:3]([CH3:2])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Agent: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A −20° C. solution of DIEA (771 mg, 5.97 mmol) and dimethylamine (2.0M in THF, 1.94 mL, 3.88 mmol) in THF (5 mL) was treated drop-wise with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (698 mg 2.98 mmol) in THF (5 mL) and stirred at RT overnight as the cooling bath expired. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine (494 mg, 84% yield). MS (ESI) m/z: 199.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([CH3:23])(C)[C:19](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C1(P([N:41]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([NH2:41])([CH3:23])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C(=O)O)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
To a mixture of the compound (1.6 g) obtained in Example 563, methylene chloride (20 ml) and triethylamine (0.92 ml), diphenylphosphorylazide (1.37 ml) was added. The reaction mixture was stirred at room temperature for 10 h and 2 N HCl and chloroform were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the resulting residue, water (16 ml) and 1,4-dioxane (32 ml) were added. The reaction mixture was heated under reflux for 2 h and 2 N HCl and chloroform were added. After adding 2 N aqueous sodium hydroxide solution and chloroform to the aqueous layer, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 1.09 g of the titled compound (yield, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH2:15])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH:15][C:26](=[O:27])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2c(Cl)cc3c(c2O1)CCC3)OCc1ccccc1
Yield: 98.2 %

Procedure:
Treatment of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (1.11 g, 4.27 mmol) with diisopropylethylamine (1.65 g, 12.8 mmol) followed by benzyl chloroformate (0.87 g, 5.12 mmol) generally according to the procedure described for Intermediate 7 provided 1.5 g (98%) of (±)-benzyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as a white solid. mp 127-130° C.; Anal. calcd. for C20H20ClNO3: C, 67.13; H, 5.63; N, 3.91. Found: C, 67.03; H, 5.42; N, 3.80. Chiral HPLC separation of (±)-benzyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (Chiralcel OD, methanol:water 9:1) provided two fractions. Fraction 1 (Rt=12.714 min Chiralcel OD, methanol:water 9:1); Fraction 2 (Rt=16.644 min, Chiralcel OD, methanol:water 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.19 (t, 3H, J=7.6 Hz), 2.62 (q, 2H, J=7.6 Hz), 7.20 (d, 2H, J=8.8 Hz, 7.38 (m, 3H), 7.65-7.72 (m, 4H), 8.81 (d, 2H, 6.4 Hz), 10.06 (s,1H). MS: m/z 446.0 (M++1).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]N1C(CCC(O)=O)C(O)=O>>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:1]1[CH:2]1[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:8]1=[O:10]
Reactant: O=C(O)CCC(C(=O)O)N1Cc2ccccc2C1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Product: O=C1CCC(N2Cc3ccccc3C2=O)C(=O)N1

Procedure:
In a further method, a dialdehyde is allowed to react with glutamine and the resulting 2-(1-oxoisoindolin-2-yl)glutaric acid then cyclized to yield a 1-oxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline of Formula I:
Reaction SMILES: Br[CH2:2][C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]2[CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C.C(Cl)Cl>[N:18]1([CH2:2][C:3]2[S:17][C:6]3=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]3[CH:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc2sc(CBr)cn2c1=O
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)cn2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (Preparation 9, 159 mg) and morpholine (0.5 mL) in DMF (10 mL) is stirred for 4 h at rt. The mixture is diluted with CH2Cl2 (100 mL) and is washed with water. The organic layer is dried (MgSO4) and concentrated to afford 130 mg (80%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 324 (M+H)+. 1H NMR (DMSO) δ8.62, 8.22, 4.25, 3.75, 3.59, 2.49, 1.28.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=1)(=O)=O.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)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>[C:23]1([C:29]#[C:30][C:7]2[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)cc(C#Cc2ccccc2)cc1=O

Procedure:
A solution of 4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.0 g, 5.4 mmol), phenylacetylene (1.1 g, 11 mmol), triethylamine (3.6 mL, 25 mmol), and PdCl2(PPh3)2 (0.42 g, 0.6 mmol) in DMF (20 mL) was heated to 90° C. under inert atmosphere for 1 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as an amorphous solid (1.5 g; TLC Rf=0.35, 1:1 EtOAc:hexanes; HPLC RT=8.64 min, method A).