Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([NH:21][NH2:22])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: NN
Reactant: CCOC(=O)c1ccc(N2CCC(N(C)C)C2)cc1
Solvent: CCO
Solvent: O
Product: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Temperature: 5 °C

Procedure:
A mixture of ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate (2.0 g), hydrazine hydrate (3.8 g) and ethanol (7 ml) was boiled under reflux for 15 hours. After cooling to 5° C., the resulting precipitate was filtered off with suction. The product with the molecular weight of 248.33 (C13H20N4O) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].C(N(C(C)C)CC)(C)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(#N)C>[S:27]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[C:4]=2[CH:5]=[CH:6]1)([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a stirred solution of 4-Cyano indole (0.5 g, 3.5 mmol), diisopropylethylamine (1.8 mL, 10.5 mmol) in acetonitrile (5.0 mL), p-toluene sulfonyl chloride (0.8 g, 4.22 mmol) was added and the mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield the title compound as brown colored solid (0.95 g, 90%). [1H-NMR (CDCl3, 300 MHz): δ 8.22 (d, 1H), 7.81-7.72 (m, 3H), 7.56 (d, 1H), 7.38 (t, 1H), 7.29-7.22 (m, 2H), 6.88 (d, 1H), 2.39 (s, 3H)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Br:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Br:30])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Br
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-bromosuccinimide (0.024 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.013 g, 21%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:28][CH2:29][CH:30]1[O:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1)(C)(=O)=O.C(O)C>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH:30]4[O:35][C:34]5[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=5[O:32][CH2:31]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CS(=O)(=O)OCCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21 mmol), K2CO3 (3.5 g, 25.4 mmol) and 2-mesyloxyethyl-1,4-benzodioxan (5.5 g, 21.3 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hours. At the end of the reaction, insolubles were filtered. The solid was washed with dichloromethane (200 ml). The solutions were combined and evaporated to an oil. This crude oil was purified by flash chromatography on a silica gel column. The material thus obtained was crystal- lized from ethanol. The 2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- ethyl]-1,Sbenzodioxan crystals were collected and weighed 3.8 g, 48%, m.p.=112°-113° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(C1C=C(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1)#N>>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccccc1Br
Agent: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C#N)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate and 2-bromobenzonitrile using a method similar to that described for D5 in Description 5.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]1[C:13]([OH:15])=[O:14])=[O:5].[N+](=[CH:18][CH2:19][CH3:20])=[N-].[N+](NC(=N)N(N=O)CCC)([O-])=O>CCOCC>[SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]1[C:13]([O:15][CH2:18][CH2:19][CH3:20])=[O:14])=[O:5]
Reactant: CN1CCN(C(=O)CCS)C(C(=O)O)C1
Reactant: CCC=[N+]=[N-]
Agent: CCCN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCOCC
Product: CCCOC(=O)C1CN(C)CCN1C(=O)CCS
Reaction time: 3 h

Procedure:
To a stirred suspension of 11.6 gms. of DL-1-(3-mercapto-1-oxopropyl)-4-methylpiperazine-2-carboxylic acid in 150 ml. of ether there is added dropwise a solution of diazopropane in ether [prepared from 8.75 g. of N'-nitro-N-nitroso-N-propylguanidine by the procedure of McKay et al. Can. J. Res. 28 B, 683(1950)]. The mixture is stirred for an additional three hours, filtered and washed twice with 100 ml. of 5% aqueous sodium bicarbonate solution. The ether solution is dried over anhydrous magnesium sulfate, and then concentrated under atmospheric pressure, leaving as a residue the desired DL-1-(3-mercapto-1-oxopropyl)-4-methylpiperazine-2-carboxylic acid, n-propyl ester.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]>O>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(=O)O)c1
Solvent: O=CO
Solvent: O
Product: O=CNc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (50 ml) was added to 98% formic acid (85 ml). The mixture was stirred at room temperature for 30 mins, then 3-aminobenzoic acid (10 g, 73 mmol) was added and the mixture was stirred for one hour at room temperature. Water (850 ml) was added and the mixture was stirred overnight at room temperature. The resultant white precipitate was collected (10.66 g, 88%).
Reaction SMILES: CN(P(N(C)C)N(C)C)C.[CH3:11][O:12][CH:13]([O:22][CH3:23])[CH2:14][C@@H:15]1[C:17]([CH3:19])([CH3:18])[C@@H:16]1[CH:20]=O.[C:24](Cl)(Cl)([Cl:26])[Cl:25].O>CCCCC>[CH3:11][O:12][CH:13]([O:22][CH3:23])[CH2:14][C@H:15]1[C:17]([CH3:19])([CH3:18])[C@H:16]1[CH:20]=[C:24]([Cl:26])[Cl:25]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(C[C@H]1[C@@H](C=O)C1(C)C)OC
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Solvent: CCCCC
Product: COC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)OC
Temperature: 14 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Tri(dimethylamino)phosphine (163.2 mmol) was added with stirring at 0° C. to a solution of (1R,cis)-2-(2,2-dimethoxyethyl)-3,3-dimethylcyclopropanecarbaldehyde (65.5 mmol) and carbon tetrachloride (163.2 mmol) in n-pentane (350 ml) kept under nitrogen in a 1-l flask. After 15 minutes stirring, the mixture was warmed up to 14° C. and kept at this temperature for 15 minutes. Then, water (75 ml) was added at 14° C. and--after removal of the aqueous phase--the organic phase was washed with two 35-ml portions of water. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to give a residue (15.7 g) containing 32.1 mmol of 2-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]ethanal dimethyl acetal (100% (1R,cis), purity 51.7%, yield 49%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[C:1]([NH:5][S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([Cl:6])[CH:8]=1)(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(NS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(Cl)c1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of t-butylamine (0.6 g) and 3-chloro-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from toluene to give 1.03 g of N-t-butyl-3-chloro-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 123°-127.5° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1>>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:4])=[N:29]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Product: Cn1ccc(NC(=O)c2cc(OCc3c(-c4ccc(F)cc4)noc3CO)nn2C)n1
Yield: 68 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.28 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of 4-aminotetrahydropyran, to the title compound (80 mg, 68%) which was obtained as a white solid. MS: m/e=425.1 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.OC1CCNCC1.N1C=CN=CN=1>O>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OC1CCNCC1
Reactant: CSc1nnc(-c2ccc(N(C)C)cc2)c(-c2ccc(N(C)C)cc2)n1
Agent: c1cnncn1
Solvent: O
Product: CN(C)c1ccc(-c2nnc(N3CCC(O)CC3)nc2-c2ccc(N(C)C)cc2)cc1

Procedure:
Three grams of 5,6-bis(4-dimethylaminophenyl)-3-methylthio-1,2,4-triazine and 1.5 g. of 4-hydroxypiperidine were heated at about 150°C. for 12 hours. The reaction mixture was treated with water and the product was collected. The product was dissolved in benzene and the solution was slowly added to n-hexane. The solid which precipitated was recrystallized from ethyl acetate to yield 1.6 g. of 5,6-bis(4-dimethylaminophenyl)-3-(4-hydroxypiperidine-1,2,4-triazine, mp about 186°-188°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:23][CH2:24][CH3:25])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCI
Product: CCOC1(c2ccc(Cl)c(Cl)c2)COCCN(C(=O)OC(C)(C)C)C1

Procedure:
Using tert-butyl (6RS)-6-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (158 mg) and ethyl iodide (0.052 mL), and by a method similar to that of Example 17, step A), the title compound (160 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CC[C@@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C.C[C@H]1CCCCN1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:18][C@@H:14]2[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 38 %

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (xi), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) with (S)-2-methyl-piperidine to obtain 1.5 g (38% yield) of the title compound as a beige oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].Cl[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[I-]>CC(CC(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CNCCCCCO
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CN(CCCCCO)c1nc2ccccc2s1
Yield: 97.3 %

Procedure:
A mixture of 5-(methylamino)pentanol (0.23 mol), 2-chlorobenzothiazole (0.3 mol), sodium carbonate (0.4 g) and potssium iodide (catalytic quantity) in methylisobutylketon (1000 ml) was stirred and refluxed overnight. The reaction mixture was cooled, washed with water, dried, filtered and the filtrate was evaporated. The residue was stirred in water, acidified with HCl, stirred, washed with diisopropylether, and the acidic layer was alkalized with NH4OH. This mixture was extracted twice with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 56 g of N-(5-hydroxypentyl)-N-methyl-2-benzothiazolamine (interm. 7).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]1)=[O:12]>C1COCC1>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) and trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370 mol) in THF (100.00 mL) was charged with (N,N-dicyclohexylcarbodiimide (11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rt for an additional 16 h then stirred at 45° C. for 1 h. The reaction mixture was filtered while still warm through a fritted funnel. The cake was washed with 3 more portions of THF and the filtrate was concentrated in vacuo and was crystallized from i-PrOH (300 mL) and filtered through a fritted funnel resulting in 11.8 g, (78% yield) of the title compound as a white crystals. 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H), 2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m, 1H) 2.84 (br. 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][C:15]([OH:17])=O)[N:10]3[CH:23]=[CH:24][CH:25]=[C:9]3[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.O[N:31]1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.N.Cl>ClCCl.C(#N)C>[CH2:21]([O:20][C:18]([C:11]1([CH2:14][C:15](=[O:17])[NH2:31])[N:10]2[CH:23]=[CH:24][CH:25]=[C:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Br:1])=[CH:3][C:4]=2[F:29])[C:12]1=[O:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)C1(CC(=O)O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C1(CC(N)=O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-4-ethoxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid (21.4 g), N-hydroxysuccinimide (5.8 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g) in dichloromethane (150 ml) was stirred at 25° C. for 1 hour, and 7.8% (w/w) ammonia in acetonitrile (40 ml) was added. The resulting mixture was stirred at 25° C. for 1 hour, poured into 5% hydrochloric acid, and extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (18.5 g, 86.4%) as colorless crystals, mp 190°-192° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])[C:7]2=[O:12].[CH2:26](OCC)C.[N+](=C)=[N-]>CO>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([O:17][CH3:26])=[O:16])[C:7]2=[O:12]
Reactant: COc1cc(C)cc(C(=O)O)c1C1=CC(=O)c2c(O)cccc2C1=O
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(C)cc(OC)c1C1=CC(=O)c2c(O)cccc2C1=O

Procedure:
In methanol (50 ml) was dissolved 2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid (1 g) as obtained in Example 15, followed by addition of a diethyl ether solution of diazomethane (20 ml). The mixture was allowed to stand at room temperature for an hour, after which the diethyl ether and methanol were distilled off. The residue was subjected to silical gel chromatography and recrystallized from diethyl ether-n-hexane. The procedure yielded yellow crystals (500 mg) of methyl 2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Li].[CH2:16]([Si:20]([CH2:23][CH2:24][CH2:25][CH3:26])(Cl)Cl)[CH2:17][CH2:18][CH3:19].[Cl-].[NH4+]>C(OCC)C>[CH2:16]([Si:20]([CH2:12][CH2:11][CH2:10][CH3:9])([CH:23]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:24]1=[CH:25][CH:26]=[CH:8][CH:7]=2)[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCC[Si](Cl)(Cl)CCCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Si](CCCC)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Fluorene (23.27 g, 140 mmol) was dissolved in 100 mL diethyl ether and the solution was cooled to −78° C. Methyllithium (1.4M in diethyl ether, 140 mL) was added dropwise to the stirred solution while maintaining the temperature at −78° C. After the addition was complete, the solution was allowed to warm to room temperature. Stirring was continued overnight. In a separate flask, di-n-butyldichlorosilane (14.9 g, 70 mmol) was dissolved in 50 mL diethyl ether. The temperature was reduced to −78° C., and the solution (prepared above) containing the fluorene anion was added to this stirred solution, dropwise. After the addition was complete, the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was then treated with a saturated solution of ammonium chloride, the organic layer was collected and dried over magnesium sulfate, and dried in vacuo. The material was further purified by washing with methanol and drying in vacuo. Yield: 23.39 g (70.7%, 97% purity by GCMS).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.O>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1
Reactant: CCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-iodophenyl)propanoic acid (35.1 g) was dissolved in DMF (200 mL) and to the resulting solution was added N-ethylmorpholine (17.0 mL) followed by TBTU (28.8 g). The mixture was stirred at room temperature for 0.5 h and then cooled to 0° C. 0.88 Ammonia (11.1 mL) was added and the mixture was allowed to warm to room temperature. The mixture was allowed to stir at room temperature for 16 h and was then poured into water and the resulting precipitate removed by filtration. The solid was dried in vacuo to give the sub-titled compound (34.2 g).
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1COCC1.O>[CH3:1][NH:2][S:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of MeNH2 (10 mL of a 2N solution in THF) and 10 mL of H2O was treated with a solution of 3-nitrobenzene sulfonyl chloride (884 mg, 4 mmole) in 4 mL of THF. The reaction was stirred for 2 hours, diluted with H2O and extracted with Et2O. The extracts were washed with H2O, 0.1N HCl, aqueous NaHCO3, dried, and the solvent removed, and gave the titled product, 608 mg (70%). MS (ESI) 217 (MH+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7](S(C)=O)[N:6]=1)([CH3:3])[CH3:2].C(NC1C(C(N)=O)=CN=C(S(C)(=O)=O)N=1)(C)C.CN1C(=O)CCC1.Cl.[NH2:42][C:43]12[CH2:50][CH2:49][C:46]([OH:51])([CH2:47][CH2:48]1)[CH2:45][CH2:44]2.CCN(C(C)C)C(C)C>>[OH:51][C:46]12[CH2:49][CH2:50][C:43]([NH:42][C:7]3[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=3)([CH2:48][CH2:47]1)[CH2:44][CH2:45]2
Reactant: NC12CCC(O)(CC1)CC2
Reactant: CC(C)Nc1nc(S(C)=O)ncc1C(N)=O
Agent: CC(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nc(NC23CCC(O)(CC2)CC3)ncc1C(N)=O
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To the solution of 4-(isopropylamino)-2-(methylsulfinyl)-pyrimidine-5-carboxamide and 4-(isopropylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide in NMP (from previous step, 2.8 mmol), 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (500 mg, 2.8 mmol), DIEA (1.1 g, 8.4 mmol) were added and heated at 100° C. for 3 d. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography to afford the final product (74.1 mg, 8.2% yield). 1H NMR (DMSO-d6) δ ppm 8.88 (br s, 1H), 8.31 (s, 1H), 7.5-6.5 (br s, 2H), 5.76 (s, 1H), 4:25 (s, 4.11 (brs, 1H), 2.05-1.97 (m, 6H), 1.61-1.54 (m, 6H), 1.24-1.12 (m, 6H); MS (ESI) m/z 320.2 [M+H]+; Purity=96.5% at 214 nm, Purity=97.7% at 254 nm.