Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>C(OCC)C.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:18]=[O:19])=[N:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2scnc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1nc2cc(F)ccc2s1
Temperature: -50 °C

Procedure:
To a stirred solution of 36 g of 5-fluorobenzothiazole in 100 ml of diethyl ether cooled to -70° C. was added dropwise over a 5 minute period 9.4 ml of a 2.5M solution of n-butyl lithium in hexane. The reaction mixture was allowed to warm to -50° C. for one hour and was then cooled to -78° C. Dry dimethylformamide (2.8 ml) was added dropwise and the reaction mixture allowed to warm to room temperature over a period of two hours. The reaction was diluted with 300 ml of diethyl ether and washed with 1N hydrochloric acid (1×40 ml), water (1×40 ml), a saturated sodium bicarbonate solution (1×40 ml) and dried over magnesium sulfate. The solvent was removed and the residual product flash chromatographed on silica (50% ethyl acetate--hexane; v:v) to give 24.7 g of the titled product, m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O)=[O:6])[CH2:2][CH3:3].Cl>O1CCOCC1>[CH2:21]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][NH2:12])=[O:6])[CH2:22][CH3:23]
Reactant: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(CCC)C(=O)COC(=O)CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled stirred solution of 3-tert-butoxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester (step 1) (36.5 g, 110 mmol) in dry dioxane under N2 was added dropwise 4N HCl in dioxane (18.12 ml, 597 mmol). The resulting mixture was allowed to warm to RT and stirred overnight. The solvent was removed in vacuo and the crude product was suspended in EtOAc (500 ml) and sonicated for 1 h. The resulting white precipitate was isolated by filtration and was dried under vacuum at 40° C. for 1 h to afford a pale yellow solid. Recrystallisation from EtOAc afforded the title compound; LC-MS Rt 0.77 mins; 231.2 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].C(N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](Cl)=[O:24]>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH:10][C:23]([C:22]1[CH:26]=[CH:27][N:28]=[C:20]([Cl:19])[CH:21]=1)=[O:24]
Reactant: COC(=O)c1cccnc1N
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccnc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A stirred and chilled (0° C.) mixture of 2-amino-nicotinic acid methyl ester (11 g, 72.3 mmol) in dichloromethane was treated sequentially with triethylamine (11 mL, 79.5 mmol) and a solution of 2-chloro-isonicotinoyl chloride (12.73 g, 72.3 mmol) in dichloromethane, such that the total volume of solvent was 80 mL. The reaction was warmed to room temperature and on completion of the reaction was quenched by addition of water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated in vacuo. The residue was suspended in hot hexane, filtered while hot and the resulting solid recrystallised from EtOH, to give 2-[(2-chloro-pyridine-4-carbonyl)-amino]-nicotinic acid methyl ester (12.76 g); 1H-NMR (300 MHz, d6-DMSO) 11.47 (1H, s), 8.62-8.67 (2H, m), 8.20 (1H, unresolved dd), 7.99 (1H, s), 7.89 (1H, unresolved dd), 7.43 (1H, dd), 3.72 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:29][OH:30].C(N(CC)CC)C>O1CCCC1.CO>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]([NH:29][OH:30])=[NH:5]
Reactant: NO
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(F)c1
Temperature: 60 °C
Yield: 83.2 %

Procedure:
153 mg of 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile were dissolved in a mixture of 1 ml tetrahydrofuran and 2 ml methanol. 265 mg hydroxylamine hydrochloride was added followed by the addition of 0.5 ml triethylamine. The reaction mixture was stirred at 60° C. for twenty hours. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 138 mg of 2-Fluoro-N-hydroxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzamidine as crude material.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([OH:21])=O)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+:2]=[N-:3].C[N:23](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[N:1]([C:4]1[S:5][C:6]([C:19]([NH2:23])=[O:21])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)s1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(N)=O)s1
Reaction time: 2.25 h
Yield: 83.8 %

Procedure:
A solution of 2.20 g (7.01 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid, 38 mL of dimethylformamide, 3.47 g (8.85 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 3.75 mL (21.53 mmole) of ethyldiisopropylamine was stirred at room temperature for 23 minutes, then 0.5733 g (10.72 mmole) of ammonium chloride was added. The mixture was stirred for 2.25 hours, then concentrated under reduced pressure and partitioned between 300 mL of ethyl acetate and 75 mL of water. The ethyl acetate layer was washed twice with 60 mL of water, twice with 55 mL of saturated aqueous sodium bicarbonate, once with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-100-:0) to give 1.841 g 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide as a light yellow solid.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5](=[O:17])[C:6]2[C:15]([CH:16]=1)=[N:14][CH:13]=[C:12]1[C:7]=2[CH:8]=[CH:9][CH:10]=[CH:11]1>Br>[OH:2][C:3]1[NH:4][C:5](=[O:17])[C:6]2[C:15]([CH:16]=1)=[N:14][CH:13]=[C:12]1[C:7]=2[CH:8]=[CH:9][CH:10]=[CH:11]1
Reactant: COc1cc2ncc3ccccc3c2c(=O)[nH]1
Agent: Br
Product: O=c1[nH]c(O)cc2ncc3ccccc3c12
Temperature: 100 °C

Procedure:
The methyl ether 4c (500 mg, 2.2 mmol) was dissolved in 10 mL HBr (48% in HOAc) in a sealed tube. The reaction was heated to 100° C. for 10 h. After cooling, the reaction was filtered and washed with acetic acid (3×10 mL) and dried in vacuo. The dry weight of the hydrobromide salt 4d was 421 mg, (90%). 1H NMR (d6-DMSO) δ 11.61 (bs, 1H), 10.50 (bs, 1H), 8.62 (d, 1H), 8.30 (d, 1H), 7.89 (t, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 6.81 (d, 1H). Anal Calcd. For C12H9BrN2O2: C, 49.17; H, 3.09; N, 9.56. Found: C, 48.75; H, 3.15; N, 9.36.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:16])[CH:11]=[C:12]([F:15])[C:13]=1[F:14].Br[C:18]([F:25])([F:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[O:16][C:18]([F:25])([F:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(F)(F)Oc1cc(F)c(F)c(F)c1
Yield: 69.4 %

Procedure:
Under a nitrogen atmosphere, 17 g of potassium carbonate and 4.0 g of TBAB were added to 18 g of 3,4,5-trifluorophenol (r-7) dissolved in 200 mL of DMF, 25.0 g of ethyl bromodifluoroacetate dissolved in 50 mL of DMF was added thereto, and the resultant mixture was stirred at 90° C. for 3 hours. A reaction mixture was poured into water, subjected to extraction with diethyl ether, and extracted organic layers were combined and washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and thus 22.8 g of ethyl 2-(3,4,5-trifluorophenoxy)-2,2-difluoroacetate (compound (r-8)) was obtained.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)[CH:39]=[CH:40][C:41]=1[F:42]>>[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 32 was prepared analogous to compound of example 8 by hydrolysis of compound of example 31.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([OH:9])=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(Br)c(F)cc1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(F)c(Br)cc1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To CH2Cl2 (30 mL) in a 50 mL round bottom flask was added 4-bromo-5-fluoro-2-methoxyphenol (2 g, 9.05 mmol). The reaction mixture was cooled to 0° C. in an ice/water bath. Boron tribromide (1.027 mL, 10.86 mmol) was slowly added via syringe over 5 min, and the ice/water bath was removed. The reaction mixture was allowed to warm to room temperature and was stirred for 18 h. The reaction mixture was placed in an ice/water bath and methanol (30 mL) was slowly added via syringe. Upon removal of the ice/water bath, the reaction mixture was allowed to warm to room temperature. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (200 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4 and filtered. Concentration of the organic solution gave 4-bromo-5-fluorobenzene-1,2-diol as a dark brown oil (1.8 g, 96%): 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=6.5 Hz, 1H), 6.72 (dd, J=8.3, 3.5 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −115.91 (s); ESIMS m/z 207 ([M+H]+), 206 ([M−H]−).
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].C1(C)C=CC=CC=1.[Cl-]>CN(C=O)C>[N:14]([CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:15]=[N-:16]
Reactant: N#Cc1ccc2c(c1)OCCC2Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCC2N=[N+]=[N-]
Temperature: 80 °C

Procedure:
4-Chloro-7-cyanochroman (Step C) (8.1 g, 42 mmol) was dissolved in dry DMF (90 mL) and NaN3 (4.0 g, 62 mmol) was added and the reaction was heated to 80° C. under N2. After 5 h TLC (SiO2, toluene) showed that no starting chloride was present. The reaction was cooled and partitioned between EtOAc (200 mL) and H2O (150 mL). The organic phase was washed with H2O (2×100 mL) and brine (100 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (SiO2, 15% EtOAc in hexane) to provide the title compound.
Reaction SMILES: C(S1C=C(C)NC1(C1N(C2C=NC=CC=2)C=NC=1)C1C=CC=CC=1)C1C=CC=CC=1.C([N:38]1[C:42]([C:43]2[S:47][C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:45][C:44]=2[CH3:54])=[CH:41][N:40]=[C:39]1[C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1)C1C=CC=CC=1.[H][H]>CO>[CH3:54][C:44]1[N:45]=[C:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:47][C:43]=1[C:42]1[NH:38][C:39]([C:55]2[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=2)=[N:40][CH:41]=1
Reactant: [H][H]
Reactant: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)n1Cc1ccccc1
Agent: CC1=C[SH](Cc2ccccc2)C(c2ccccc2)(c2cncn2-c2cccnc2)N1
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)[nH]1
Reaction time: 70 h

Procedure:
The title compound is prepared from 5-(1-benzyl-2-(pyridin-3-yl-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole (Example 71) in a similar manner as described in Tetrahedron Letters, 2008, 64(26), 6060-6072. In this case, 5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole in methanol is debenzylated by hydrogenation under an atmospheric pressure of hydrogen using a balloon with vigorous stirring for 70 h under reflux. The reaction mixture is filtered through Celite, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to give the title compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][C:33]2[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=2)[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:59](=[O:60])[N:42]2[C:43]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[C:44]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH2:45][S:46][C@H:41]12.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][C:33]2[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=2)[C:27]([NH:39][C@@H:40]2[C:59](=[O:60])[N:42]3[C:43]([C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])=[C:44]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[CH2:45][S:46][C@H:41]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1cncc1CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOCc3cncn3C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Yield: 77.9 %

Procedure:
5.23 g of 2-(2-tritylaminothiazol-4-yl)-2-((1-methylimidazol-5-yl)methoxyimino)acetic acid and 3.28 g of tertiary butyl 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylate were suspended in 200 ml of methylene chloride and 1.35 g of 1-hydroxybenzotriazole was added thereto. A mixture of 2.27 g of DCC and 20 ml of methylene chloride was added to the mixture under stirring and cooling in an ice-bath. The resulting mixture was stirred for 1 hour at the same temperature and then stirred for 23 hours at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography with a 1% methanol-chloroform eluent to give 6.49 g of tertiary butyl 7β-(2-(2-tritylaminothiazol-4-yl)-2-((1-methylimidazol-5-yl)methoxyimino)acetamido)-3-acetoxymethyl-3-cephem-4-carboxylate (syn isomer) as a powder.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc21
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C([C@@H]1CCCN1C(=O)CC1CCc2ccccc21)N1CCCC1
Yield: 62 %

Procedure:
A colorless oil of 1-[1-(2-indanylacetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indanylacetyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 62%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH:6]([O:69][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:77])[CH3:2].[N-:78]=[N+:79]=[N-:80].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:78]=[N+:79]=[N-:80])[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH:6]([OH:69])[CH2:5][C:4]1=[O:77])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 34.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (68 mg) in N,N-dimethyl formamide (1 ml) was added an excess of sodium azide (20 mg) and the mixture heated to 70° C. After 4 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (17.5 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=O)[C:4](=[CH:8][C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27]C)=[O:25])[CH2:20][CH2:19]3)[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[NH:3]1>CN(C)C=O.[Pd]>[O:1]=[C:2]1[NH:6][C:5]2=[N:15][C:14]3[CH:13]=[CH:12][C:11]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]4)=[CH:10][C:9]=3[CH:8]=[C:4]2[NH:3]1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1
Reaction time: 42 h

Procedure:
Ethyl 1-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenyl]-4-piperidinecarboxylate (35.8 g, 92 mmol) in dimethylformamide (500 mL) was hydrogenated over 10% palladium on charcoal (3.6 g) at 200 psi pressure. After 42 hours, the mixture was filtered through kieselguhr, the solvent evaporated, and the residue diluted with 50% methanol/ether ether (500 mL). A light spray powder (25.0 g) was collected in two crops. The powder was added to methanol (500 mL) containing p-toluene sulfonic acid (1.5 g), and heated at reflux for 18 hours. Upon cooling, the mixture was filtered to give 19.5 g of an off white solid consisting of a mixture of ethyl 1-(1,3,9,9a-tetrahydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)-4-piperidinecarboxylate and the corresponding oxidized 2,3-dihydro compound (ethyl ester of the title compound). The solid was added to methanol (500 mL), heated to reflux, iodine (13.7 g, 54 mmol) added portionwise, and reflux continued for 2.5 hours. Upon cooling, 10% sodium thiosulfate and 10% sodium carbonate solution were added until pH=7. Water (300 mL) was added, and the precipitate consisting of the title compound collected (19.4 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[N+:21]([O-])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP(OCC)OCC)C>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:11]3[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)[NH:21][C:6]=2[CH:7]=1
Reactant: COc1ccc(-c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Agent: CCOP(OCC)OCC
Product: COc1cc2[nH]c3cc(OC)c(OC)cc3c2cc1OC
Yield: 33.1 %

Procedure:
1,2,6,7-Tetramethoxy-9H-carbazole/2,3,6,7-Tetramethoxy-9H-carbazole—A stirred solution of 2-((3,4-dimethoxy)phenyl)-4,5,-dimethoxynitrobenzene (6.5 g, 20 mmol) in triethylphosphite (10.5 mL, 6.11 mmol) was heated at 160° C. under a nitrogen atmosphere for 10 hours. The excess triethylphosphite was removed in vacuo, residue was slurried in chloroform the solids were filtered and recrystallized from EtOAc to afford 2,3,6,7-tetramethoxy-9H-carbazole (1.9 g); m.p. 232-233° C. Anal. Calcd. for C16H17NO4: C, 66.88; H, 5.97; N, 4.88. Found: C, 65.04; H, 5.62; N, 4.71. The chloroform filtrate from above was concentrated in vacuo and flash chromatographed (20% EtOAc/CCl4) to afford 1,2,6,7-tetramethoxy-9H-carbazole (1.7 g); m.p. 170-171° C. (MeOH). Anal. Calcd. for C16H17NO4: C, 66.88; H, 5.97; N, 4.88. Found: C, 66.75; H, 5.80; N, 4.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[N+:20]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(-c2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylboronic acid (24.54 g), 4-chloro-3-nitropyridine hydrochloride (26.24 g), Pd(Ph3P)4 (4 g) and K2CO3 (111 g) were combined in DME (500 mL). The reaction was heated to reflux for 10 hours. After the mixture cooled down to room temperature, it was poured into saturated aqueous NH4OAc (500 mL) solution. The aqueous phase was extracted with EtOAc (3×200 mL). The combined extract was concentrated to give a residue which was purified using silica gel chromatography (10% to 30% EtOAc/PE) to afford 10.6 g of Precursor 1, 3-Nitro-4-(4-methoxyphenyl)pyridine. MS m/z: (M+H)+ calcd for C12H11N2O3: 231.08; found 231.02. HPLC retention time: 1.07 minutes (column B).