Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5]([N:7]2[CH2:13][CH2:12][CH:11]3[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][N:10]3[C:9]3[N:25]=[CH:26][CH:27]=[CH:28][C:8]2=3)=[O:6])[CH2:4][CH2:3]1>C(Cl)Cl>[CH:2]1([C:5]([N:7]2[CH2:13][CH2:12][CH:11]3[CH2:14][NH:15][CH2:16][CH2:17][N:10]3[C:9]3[N:25]=[CH:26][CH:27]=[CH:28][C:8]2=3)=[O:6])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3N(C(=O)C3CC3)CCC2C1
Agent: Cl
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2CNCCN2c2ncccc21
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A solution of HCl (4 M in dioxane, 250 μl, 1 mmol) was added to a solution of the product of Example 72B (26.3 mg, 0.071 mmol) in CH2Cl2 (1.3 mL), and the mixture was stirred at room temperature for 70 hours. The mixture was concentrated under vacuum, and the residue was crystallized from ethyl acetate-ethanol (4 mL, 2:1) to provide the title compound as the bis-hydrochloride salt: 1H NMR (400 MHz, pyridine-d5, 110° C.) δ ppm 0.41 (dd, J=7.8, 3.5 Hz, 2H), 0.85-0.97 (m, 2H), 1.06-1.21 (m, 1H), 1.51-1.64 (m, 1H), 1.66-1.77 (m, 1H), 2.91 (t, J=11.0 Hz, 1H), 3.25-3.45 (m, 3H), 3.53-4.09 (m, 5H), 6.77 (dd, J=7.6, 4.9 Hz, 1H), 7.37 (dd, J=7.6, 1.5 Hz, 1H), 8.16 (dd, J=4.6, 1.5 Hz, 1H); MS (DCI) m/z 273 (M+H)+. Elemental analysis is calculated for C15H20N4O.2 HCl.0.5H2O.0.4 EtOAc: C, 51.19; H, 6.78; N, 14.38. Found: C, 51.23; H, 6.57; N, 14.12.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=1[Cl:54].BrCC1OC(C(F)(F)F)=CC=1>>[Cl:54][C:48]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:47]=1[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(F)cc2Cl)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-chloro-4-fluorobenzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (54%) as a white solid: mp 174-175° C.; MS (ES+) m/z 424.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11](O)=[O:12].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][N:4]=1)=[O:12]
Reactant: Cc1cnc(N)s1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(Cl)ccc2Cl)s1
Temperature: 22 °C
Reaction time: 14 h
Yield: 79.1 %

Procedure:
To a solution of 5-methylthiazole-2-amine (Aldrich, 1.0 g, 8.76 mmol) in tetrahydrofuran (10 mL) was added 2,5-dichlorobenzoic acid (Aldrich) (2.01 g, 10.51 mmol), triethylamine (2.93 mL, 21.02 mmol), and 1-propanephosphonic acid cyclic anhydride (Aldrich, 50% solution in ethyl acetate, 6.19 mL, 10.51 mmol). The reaction mixture was stirred at 22° C. for 14 h., cooled, and quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 1.99 g of the title compound. MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH2:44])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47].[C:48](OC(=O)C)(=[O:50])[CH3:49].O>CO>[CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH:44][C:48]([CH3:49])=[O:50])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47]
Reactant: CO[C@@H]1[C@@H](N)[C@@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)O[C@H](C)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: CO[C@H]1[C@@H](O)[C@@H](C)O[C@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)[C@@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of elsamicin A (65.4 mg) and acetic anhydride (0.1 ml) in dry methanol (2 ml) was stirred at room temperature for 1 hour. Water (1 ml) was added and the mixture was evaporated in vacuo to give a yellow oil, which was purified by column chromatography on silica gel to give 70.5mg (100%) of the desired product.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(O)(=O)C>[Zn].O>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2sc(C(=O)N[C@@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
422 mg (1.15 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzothiophene-2-carboxamide hydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid and water. 300.0 mg (4.59 mmol) of zinc are added, the mixture is then stirred at RT for 1 h. The reaction mixture is filtered through kieselguhr, and the filter cake is washed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by preparative HPLC. The product fraction is dissolved in 4M of HCl in dioxane, concentrated under reduced pressure and recrystallized from acetonitrile. 203 mg (47.3% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 62.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]2[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[N:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:13]=[CH:12][CH:11]=1)[CH2:23][C:22]2([CH3:25])[CH3:24])#[N:27]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Ethanesulfonyl chloride (104 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford ethanesulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (120 mg, yield: 60.0%). MS (ESI+APCI) M+1=370.2.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[S:15]1[CH:19]=[N:18][N:17]=[C:16]1[NH:20]N(C=S)C(=O)OC1C=CC=CC=1>C(#N)C>[S:15]1[CH:19]=[N:18][N:17]=[C:16]1[NH:20][C:2]([NH:3][C:6](=[O:7])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:1]
Reactant: O=C(Oc1ccccc1)N(C=S)Nc1nncs1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC#N
Product: O=C(NC(=S)Nc1nncs1)Oc1ccccc1
Temperature: 24 °C
Reaction time: 2 h

Procedure:
A solution of 3.8 g (50 mM) of ammonium thiocyanate in 100 ml of acetonitrile containing 7.8 g (50 mM) of phenyl chloroformate was stirred at 24° C. for one hour. The reaction mixture was filtered into a suspension of 6.88 g (50 mM) of 2-amino-1,3,4-thiadiazole hydrochloride in 75 ml of acetonitrile and 25 ml of propylene oxide. The reaction mixture was stirred for two hours at 24° C. and then filtered to provide a solid precipitate identified as 6.42 g of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl carbamic acid, phenyl ester.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C:5]([CH3:17])([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:4]1=[O:18])[CH3:2].C(O)C.[H][H]>[Pd].CCCCCC.CCOC(C)=O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2([CH3:17])[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[C:4]2=[O:18])=[CH:9][CH:10]=1
Reactant: CCN1CCC(C)(c2ccc([N+](=O)[O-])cc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1CCC(C)(c2ccc(N)cc2)C1=O

Procedure:
A mixture of 770 mg (3.1 mmol) (±)-1-ethyl-3-methyl-3-(4-nitrophenyl)pyrrolidin-2-one, 50 mg of 10% palladium on carbon, and 50 mL of absolute ethanol was shaken with hydrogen (initial hydrogen pressure 46 psig) in a pressure vessel for 2.5 hours. The catalyst was removed by filtration through Celite under nitrogen, and the filter cake was washed with additional ethanol. Concentration of the filtrate in vacuo gave 684 mg (quantitative) of an extremely pale pink oil; essentially homogeneous by TLC in 1:1 hexane-EtOAc. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=219.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10].[CH2:12](N)[CH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]1[NH:14][CH2:13][CH2:12][N:10]=1)[CH3:11]
Reactant: CC(C#N)c1ccccc1Br
Reactant: NCCN
Product: CC(C1=NCCN1)c1ccccc1Br

Procedure:
rac-2-[1-(2-Bromo-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-bromo-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): off-white solid; MS (EI): 251.0 and 253.0 (M+.), 173.1 (((M-Br)+.), 100%).
Reaction SMILES: NC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O.[C@@H:20]1([N:28]2[C:38]3[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=3[N:30]=[CH:29]2)[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[CH2:21]1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=[O:51].[N-:61]=[N+:62]=[N-:63].[Na+]>N1C=CC=CC=1.CN(C=O)C>[N:61]([CH:25]([OH:26])[C@H:24]1[O:27][C@@H:20]([N:28]2[C:38]3[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=3[N:30]=[CH:29]2)[C@H:21]([OH:51])[C@@H:22]1[OH:23])=[N+:62]=[N-:63]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: NC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(O)[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](O)[C@@H]1O

Procedure:
An alternate preparation of 5'-amino-2',5'-dideoxyguanosine is to treat the protected 2'-deoxyguanosine (protected at either the N-2-phenylacetyl or the N-2-FMOC derivative) (1 mmol) with tosyl chloride (1.3 mmol) in pyridine at 0° C. overnight. The solution is evaporated to dryness and the residue is dissolved in chloroform. The resulting solution is washed twice with aqueous sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated and the residue chromatographed on silica gel eluting with methanol/chloroform mixtures. The resulting tosylate (1 mmol) is treated with sodium azide (6 mmol) in DMF at 80°-100° C. for a few h. The solvent is removed by rotovap and the residue is chromatographed on silica gel eluting with chloroform/ methanol solvent mixtures. The azide is reduced to the desired amine using the catalytic hydrogenation procedure above.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:23][C:24]4[N:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCC(O)CC2)cn1
Reactant: CCc1cc2cnc(S(C)(=O)=O)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Product: CCc1cc2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 140 °C
Yield: 7.3 %

Procedure:
8-Cyclopentyl-6-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.115 g, 0.47 mmol) and 6′-amino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (0.117 g, 0.61 mmol) were combined in dry xylenes and heated at 140° C. under nitrogen overnight. The crude reaction mixture then was allowed to cool and diluted with CH2Cl2. A precipitate was collected by filtration and dried in vacuo to give 8-cyclopentyl-6-ethyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (15 mg, 7%). MS (APCI); M++1: Calc'd, 435.2. Found 435.2.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][C:31]=1[C:40]#[N:41].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:40]#[N:41])[CH:32]=2)(=[O:37])=[O:38])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc(F)c(C#N)c1
Yield: 92 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 in CH2Cl2 (4 mL) was added 4-fluoro-3-cyanobenzenesulfonyl chloride (92 mg, 0.42 mmol) followed by NaHCO3 (40 mg) and satd. NaHCO3 (0.4 mL) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water, brine and dried with Na2SO4 and concentrated to furnish crude product (240 mg). The crude product was purified by column chromatography using 1/1 ethyl acetate/hexane to provide 200 mg product (92% yield).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:13][CH2:14][C:15]1[N:16]([CH2:29][CH2:30][OH:31])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([O:13][CH2:14][C:15]1[N:16]([CH2:29][CH:30]=[O:31])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1)[CH3:12]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CC=O
Temperature: 25 °C

Procedure:
To dichloromethane (10 mL) at −78° C. was added dimethylsulfoxide (0.37 mL, 5.17 mmol) and oxalyl chloride (0.33 mL, 3.79 mmol). After several minutes, a solution of 2-[8-(ethoxymethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]ethanol (prepared as described in U.S. Pat. No. 6,797,718, 1.00 g, 3.44 mmol) in dichloromethane (40 mL) was added dropwise followed by triethylamine (1.5 mL, 10.3 mmol). The mixture was allowed to warm to room temperature and more dichloromethane (80 mL) was added. The solution was transferred to a separatory funnel and washed with saturated aqueous potassium carbonate, water, and brine. The aqueous layers were combined and back-extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the product [8-(ethoxymethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]acetaldehyde as a tan solid (0.86 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][C:21]2=[O:30])[CH:14]=1.CO.[Li+].[OH-].Cl>O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2=[CH:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:31]
Reactant: COC(=O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
8-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)octanoic acid methyl ester (438 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (305 mg, 72% yield) as a brown solid. LC-MS (m/z) 425 (M+1).
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]2)=[O:6])[CH:3]=1.C(OO[C:41]([CH3:44])([CH3:43])C)(C)(C)C>C1CCCCC1>[C:5]([O:7][CH:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([O:16][CH:43]2[CH2:41][CH2:44][CH2:13][CH2:8][CH2:9]2)[C:10]([CH3:18])([CH3:17])[CH2:9]1)(=[O:6])[C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([C:1]([O:23][CH:24]2[CH2:25][C:26]([CH3:34])([CH3:33])[N:27]([O:32][CH:2]3[CH2:21][CH2:20][CH2:19][CH2:4][CH2:3]3)[C:28]([CH3:31])([CH3:30])[CH2:29]2)=[O:22])[CH:3]=1
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(O)C(C)(C)C3)c2)CC(C)(C)N1O
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)c2)CC(C)(C)N1OC1CCCCC1

Procedure:
A solution of 34.2 g of di-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) isophthalate and 54 ml of di-tert-butyl peroxide in 250 ml of cyclohexane is heated for 22 hours in a nitrogen atmosphere in a Fisher-Porter bottle (bath temperature of 140° C.). Solvent is evaporated under reduced pressure. The product is recrystallized from pentane to give a white solid, mp 140°-42° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1)[CH3:4].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][Cl:1])[N:10]=1)[CH3:4]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1nc(CCl)cs1

Procedure:
The methanols produced by the process of this example are readily converted to the corresponding thiazolemethyl chlorides according to the following procedure: A suspension was prepared from 1.05 grams of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride and 15 ml. of chloroform. Thionyl chloride (2.50 g) was added and the resulting mixture was stirred at reflux temperature for about 2.75 hours. Any volatile constituents including excess thionyl chloride were removed by evaporation. The residue was suspended in chloroform and the chloroform removed by evaporation. The residue was then recrystallized from a methanol-ethyl acetate solvent mixture to yield 2-dimethylaminomethyl-4-thiazolylmethylchloride hydrochloride melting at 136°-8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C.O.CCOCC>[F:17][CH:13]([F:18])[O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3.14 g (20.0 mmol) 5-fluoro-2-nitrophenol in 36 mL of DMF are added 6.1 g (40.0 mmol) of sodium chlorodifluoroacetate and 3.31 g (24.0 mmol) of powdered sodium carbonate. The reaction mixture is heated at 100°C. for 4 hours 30 minutes and is then allowed to cool to room temperature. Aqueous 4N HCl solution is added and the mixture is stirred at room temperature for 2 hours. The resulting mixture is diluted with 100 mL of water and 100 mL of ether. The aqueous phase is extracted with ether and the organic phases are then combined, washed with aqueous 1N NaOH solution and then with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 3.68 g of the expected product are obtained in the form of a yellow oil, which is used as obtained in the following step. Yield=89%.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:27](=[CH:28][CH:29]=1)[O:26][C:20]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:19]/[C:18]/2=[N:30]\[S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=[O:32]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]2[C:27](=[CH:28][CH:29]=1)[O:26][C:20]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:19][C:18]2([CH2:2][C:1]([O:4][CH3:5])=[O:3])[NH:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)S(=O)(=O)/N=C1\CC2(CCCCC2)Oc2ccc(Br)cc21
Reactant: COC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1(NS(=O)C(C)(C)C)CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of methyl acetate (1.86 g, 0.025 mol) in THF (18 mL) was added LDA (2 M in THF) was added dropwise via a syring at −78° C. After stirring at −78° C. for 30 minutes, a solution of (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfonamide (5.0 g, 0.0126 mol) in THF (7.4 mL) was added dropwise via a syring. The mixture was stirring at −78° C. for 3 h. The reaction was quenched with aqueous NH4Cl solution and allowed to warming to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give the product, which was purified by chromatography to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate (1.4 g, 33%). 1H NMR (CDCl3): 1.23 (s, 9H), 1.36-1.52 (m, 4H), 1.57 (m, 1H), 1.66 (m, 3H), 1.86 (d, 2H), 2.24 (d, 1H), 2.67 (d, 1H), 2.93 (s, 3H), 3.71 (s, 3H), 5.34 (s, 1H), 6.79 (d, 1H), 7.26 (s, 1H), 7.39 (s, 1H).