Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:40])[NH:12][C:13]([C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:36][OH:37])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.CCOC(C)=O>C1COCC1>[C:6]([O:10][C:11]([NH:12][C:13](=[NH:14])[C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[O:40])([CH3:8])([CH3:9])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COS(C)(=O)=O)c1
Reaction time: 18 h
Yield: 14.8 %

Procedure:
Methanesulfonyl chloride (0.027 g, 0.241 mmol) was added to a solution of {[4-(2′-hydroxymethyl-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.100 g, 0.188 mmol) [example 213, step b] and triethylamine (0.048 g, 0.470 mmol) in THF [3 mL] at room temperature and stirred for 18 hours. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.017 g, 14%). ESI-MS (m/z): Calcd. for C26H30N2O7S4: 610.09; found: 611.8.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18](OC)=[O:19])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1.O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[O:19])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cn1cc(Cc2ccccc2)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=CCn1cc(Cc2ccccc2)c2ccccc21
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step 1 (470 mg, 1.68 mmol) in toluene (15 mL) at -65° C. there was slowly added 1.0M DIBAL in toluene (2.24 mL, 2.24 mmol) and the mixture was stirred at -65° C. for 1 hour. There was slowly added MeOH (5 mL) and the mixture was then allowed to warm up to r.t. There was added H2O (20 mL) and 1N aqueous HCl (10 mL) and after shaking the organic phase was washed with H2O, dried over MgSO4 and evaporated down to an oily residue which was taken as such to the next step.
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19](/[C:22](=O)[CH3:23])\[C:20]#[N:21])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]3[C:19]([C:20]#[N:21])=[C:22]([CH3:23])[NH:29][C:3]4[CH2:4][CH2:5][S:1](=[O:8])(=[O:7])[C:2]3=4)=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]ncc2c1
Reactant: [NH4+]
Reactant: O=C1CCS(=O)(=O)C1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2)C2=C(CCS2(=O)=O)N1

Procedure:
127 mg (0.947 mmol) dihydrothiophen-3(2H)-one-1,1-dioxide, 266 mg (0.947 mmol) (2E)-2-(1H-indazol-5-ylmethylidene)-3-oxobutanenitrile (Example 8A) and 88 mg (1.136 mmol) ammonium acetate in acetic acid (5 ml) were heated to reflux overnight. After cooling, the mixture was evaporated to dryness, and the residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 16 mg (5% of th.) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3].[NH2:22][C:23]([NH2:25])=[S:24].C(O)C.[ClH:29]>O>[ClH:29].[Si:15]([O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH2:3][NH:25][C:23](=[NH:22])[SH:24])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1c(CCCNC(=N)S)ccc2ccccc12
Yield: 86 %

Procedure:
A mixture of the product of Example 122 Part C (1.55 g, 0.004 mole), thiourea (0.31 g, 0.004 mole), and absolute ethanol (8.0 mL) was heated at reflux for 7 hours. The cooled solution was treated with water (5.0 mL), cooled to 0°, and treated with concentrated hydrochloric acid (5.0 mL). The precipitated solid was isolated by filtration, rinsed with water and air-dried to provide the title compound (1.45 g, 86%) as a white powder, mp 190°-194°.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:17]Br>CCCCC>[C:1]([N:5]=[N:6][C:7]([Br:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)=NNC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC(C)(C)Br
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 25.6 grams (0.2 mole) of acetone t-butylhydrazone and 20.3 grams (0.2 mole) of triethylamine in 200 ml of pentane, cooled to 5° C in a 500 ml 4-neck round bottom flask equipped with a mechanical stirrer and thermometer, was added 31.9 grams (0.2 mole) of bromine from an addition funnel. After the addition was complete the reaction was stirred an additional 1/2 hour at 5° C, filtered to remove the triethylamine hydrobromide and the pentane evaporated from the filtrate under reduced pressure. The residue was an orange yellow liquid weighing 40 grams (96.6% crude yield). The infrared spectrum of the residue was in agreement with the structure of 2-t-butylazo-2-bromopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:13][OH:14].Cl.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[N:13][OH:14]
Reactant: NO
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(C=NO)c1
Yield: 82.3 %

Procedure:
To 16.6 g (99.9 mmol) of 2,5-dimethoxybenzaldehyde in ethanol (100 mL) is added a mixture of 7.64 g (169 mmol) of H2NOH—HCl and 13.9 g (169 mmol) of sodium acetate in 50 mL of H2O. This reaction mixture is heated to reflux for 2.5 h. After adding H2O to dissolve the precipitated inorganic salt, ethanol is removed by evaporation in vacuo. The resulting white solid is filtered off and washed with H2O. 14.9 g of white solid are obtained (82%). 1H-NMR (CDCl3). δ [ppm]: 3.79 (s, 3H), 3.82 (s, 3H), 6.85 (d, 1H), 6.92 (d, 1H), 7.25 (d, 1H), 8.00 (broad s, 1H), 8.47 (s, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:11]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.[C:26](=[O:28])=[O:27].C1COCC1>C1COCC1>[ClH:9].[Cl:9][C:10]1[C:11]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:26]([OH:28])=[O:27]
Reactant: Clc1cnc(OCCN2CCOCC2)c(Cl)c1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(O)c1c(Cl)cnc(OCCN2CCOCC2)c1Cl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of lithium diisopropylamide (6.4 g, 0.06 mol) in THF (100 ml) under nitrogen was cooled to -70° C. and a solution of 3, 5-dichloro-2-[2-(4-morpholinyl) ethoxy]pyridine (13.0 g, 0.047 mol) in THF (10 ml) was added via syringe. The yellow/red solution was stirred for 30 minutes at -70° C. and then was slowly warmed to room temperature. The mixture was poured onto crushed dry ice/THF and upon evaporation of the dry ice the solvent was removed in vacuo. The residue was taken up in dilute ammonium hydroxide and extracted with chloroform (2X). The organic layer was separated and concentrated in vacuo to afford 6.0 g of recovered starting material. The aqueous layer was concentrated in vacuo and 3N HCl was added to the residue. The 15 solution was cooled and a solid was obtained which was collected by filtration. The solid was recrystallized from water to afford 3,5-dichloro-2-[2-(4-morpholinyl)ethoxy]pyridine-4-carboxylic acid hydrochloride as a white solid in 71% yield (based on recovered starting material), m.p. 230°-231° C. (dec.).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21]1[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])=[CH:30][C:20]2=1)=[O:16].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1COCC1.CCO.CCOC(C)=O>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21]1[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])=[CH:30][C:20]2=1)=[O:16])[CH3:10]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
940 mg (6.4 mmol) of diethyl oxalate are dissolved in 5 ml of anhydrous THF. 273 mg (6.8 mmol) of 60% NaH are added and the mixture is stirred at ambient temperature for 10 minutes. A solution of 1.3 g (3.2 mmol) of compound 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from preparation 1.2 above and 18 mg (0.052 mmol) of dibenzo-18-crown-6 dissolved in 20 ml of anhydrous THF is added, as are a few drops of anhydrous EtOH. The mixture is heated at 70° C. under argon for 3 hours. The mixture is allowed to return to ambient temperature. EtOAc is added to the reaction medium and the organic phase is washed with a 1N HCl solution. The organic phase is evaporated to dryness and the product obtained is triturated in water and filtered. The product is taken up in EtOH and evaporated to dryness.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C@H:8]([NH:13][C:14](=[O:38])[CH:15]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:9](OC)=[O:10])=[CH:5][N:4]=[CH:3]1.[CH3:39][NH2:40]>CO.O1CCCC1>[CH3:39][NH:40][C:9]([C@@H:8]([NH:13][C:14](=[O:38])[CH:15]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)=[O:10]
Reactant: COC(=O)[C@H](Cc1cncn1C)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1cncn1C)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 611 mg (1.2 mmol) of the product from Example 6 in 20 mL MeOH and 10 mL tetrahydrofuran was cooled in ice and saturated with gaseous methylamine. The cooling was removed and the solution allowed to stir at room temperature overnight. The solvent was removed under reduced pressure and the residue triturated with acetonitrile to give 529 mg of the pure product, mp 250-252° C. The structure was confirmed by NMR and mass spectroscopy; (m+H)+ =505.
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].[NH4+].CN(C)C=O.C(=S)=[S:31]>C(N(CC)CC)C>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:31])[N:13]=1
Reactant: S=C=S
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 98 %

Procedure:
In the same manner as described in Example 11, 9.6 g of adenosine 1-oxide monohydrate was treated with a 5N sodium hydroxide aqueous solution and Diaion SK-1B (ammonium-type). 60 ml of N,N-dimethylformamide and 60 ml of triethylamine were added to the resulting residue to form a solution, and 30 ml of carbon disulfide was then added to the solution. The resulting mixture was allowed to react in an autoclave at 130° C for 4 hours under autogenous pressure (about 10 kg/cm2). The reaction mixture was concentrated to dryness followed by working up in the same manner as described in Example 11 to obtain 9.35 g of 2-thioadenosine as crystals having a melting point of 198° C (with decomposition) in a 98% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:4]([C:12]([O:14]C)=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li+].[OH-].Cl.C(OCC)(=O)C>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)c(Cl)cc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2)c(Cl)cc2ccccc12
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of Example 146B in dioxane (3 mL) and water (0.3 mL) was treated with 3N LiOH (0.6 mL); stirred at 50° C. for 4 days, acidified with 1N HCl, treated with ethyl acetate, washed with brine (3×), dried (MgSO4), filtered, and concentrated and ethyl acetate was added. The ethyl acetate layer was washed with brine (3×), dried over magnesium sulfate anhydrous. The concentrate was purified by reverse phase chromatography to provide 1.5 mg of the desired product. MS (ESI(−)) m/e 346 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1C=O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a 500 mL two-neck round flask charged with 3-bromo-2-hydroxybenzaldehyde (D98) (13 g, 64.7 mmol) was added DMF (300 mL). Then K2CO3 (17.88 g, 129 mmol) was added, followed with methyl iodide (18.36 g, 129 mmol) at room temperature. The resulted mixture was stirred at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered through celite and washed with EtOAc. The resulted filtration was concentrated under reduced pressure. The residue was dissolved in EtOAc (250 mL), and washed with water (100 mL), 1N HCl (100 mL×2) and brine (100 mL×2). The organic layers was dried with sodium sulphate and concentrated. The residue was purified with ISCO column chromatography to afford 3-bromo-2-(methyloxy)benzaldehyde (D99) (4.05 g) as pale yellow oil. MS (ES): C8H7BrO2 requires 213.9. found 215.0 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:8]=[N+:9]=[N-:10].[Na+].O>C(#N)C>[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN=[N+]=[N-]

Procedure:
A solution of ethyl bromoacetate (150 g, 0.901 mol) in dry acetonitrile (800 ml) was treated with sodium azide (58.57 g, 0.901 mol) under a nitrogen atmosphere, and the mixture was heated at reflux for 20 hours. After cooling, water (50 ml) was added and the mixture was stirred for half an hour; the upper phase was separated out and the lower phase was treated with a salt and extracted with diethyl ether. The organic phases were combined and the solvent removed at a temperature not exceeding 50° C., in order to give a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([C@H:12]([OH:17])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]([O:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[C:11]([C@H:12]([O:17][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]([O:22][CH:23]([CH3:24])[CH3:25])[CH:3]=1
Reactant: C=C[C@@H](C)[C@@H](O)c1c(O)cc(OC(C)C)c2c(CCC)cc(=O)oc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=C[C@@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)c1c(O)cc(OC(C)C)c2c(CCC)cc(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
To a solution of 4a (500 mg, 1.44 mmol) in dry CH2Cl2 (20 mL) at 0° C. was added DMAP (88 mg, 0.72 mmol), imidazole (196 mg, 2.88 mmol) and tert-butylchlorodimethylsilane (239 mg, 1.59 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 24 h. Water (10 mL) was then added, the organic layer was separated, dried (MgSO4), concentrated and submitted to silica gel chromatography (Solvent B) to obtain 5a (583 mg, 88%) as a syrup: [α]D20 +38.0° (c 1.1, CHCl3); 1H NMR (CDCl3): δ -0.04 (s, 3 H, --SiCH3), 0.14 (s, 3 H, --SiCH3), 0.87 [s, 9 H, --C(CH3)3 ], 0.97 (d, 3 H, J=6.88 Hz, --CHCH3), 1.00 (t, 3 H, J=7.44 Hz, --CH2CH2CH3), 1.38 and 1.40 (2d, 6 H, J=6.0 Hz, --CH(CH3)2), 1.62 (m, 2 H, --CH2CH2CH3), 2.59 (q, 1 H, J=6.9 Hz, --CHCH3), 2.86 (bt, 2 H, --CH2CH2 CH3), 4.62 [m, 1 H, J=6.06 Hz, --CH(CH3)2 ], 4.95-5.05 (m, 2 H, --CH=CH2), 5.29 [d, 1 H, J=6.5 Hz, --CHOSi(CH3)2 --], 5.85 (m, 1 H, --CH=CH2), 5.89 (s, 1 H, H-3), 6.24 (s, 1 H, H-6), 9.15 (s, 1 H, ArOH); 13C NMR (CDCl3): δ -0.33, -0.15, 13.91, 16.27, 18.06, 21.76, 21.85, 23.08, 25.68, 25.88, 38.96, 44.62, 70.67, 74.28, 97.54, 103.39, 106.57, 109.86, 115.71, 139.60, 152.98, 156.13, 158.95, 160.17, 160.75. Anal. Calcd for C26H40 O5Si: C, 67.78; H, 8.75. Found C, 67.91; H, 8.71.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl.[NH2:28][C:29]1[S:30][CH2:31][CH2:32][N:33]=1>>[CH2:11]([O:18][C:19]1[C:20](=[O:22])[N:33]2[CH2:32][CH2:31][S:30][C:29]2=[N:28][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: NC1=NCCS1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCS2
Yield: 45.9 %

Procedure:
Reaction of diethyl oxalate (7.66 g, 52.4 mmol), ethyl benzyloxyacetate (10.2 g, 52.5 mmol) and sodium hydride (2.31 g of a 60% dispersion in mineral oil, 57.9 mmol) with 2-amino-2-thiazoline hydrochloride (7.28 g, 52.5 mmol) as described in intermediate 1 gave 7.99 g (46% yield) of the title ester as white crystals; mp 117 118° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH3), 3.52 (2H, t, J=7.6 Hz, CH2), 4.34 (2H, q, J=7.1 Hz, OCH2), 4.49 (2H, t, J=7.6 Hz, CH2), 5.22 (2H, s, OCH2), 7.3–7.51 (5H, m, aromatics). Anal. Calcd for C16H16N2O4S: C, 57.81; H, 4.85; N, 8.42. Found: C, 57.78; H, 4.76; N, 8.30.
Reaction SMILES: CN(C)C(=O)[O:4][CH:5]([C:10]1[N:11]([CH3:31])[C:12]([C:21]2[S:22][C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH2:30])[C:28]=3[N:29]=2)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].CN(C)C(=O)OC(C1N(C)C(C2SC3N=CN=C(N)C=3N=2)=C(C2C=CC=CC=2)N=1)C1C=CC=CC=1>>[NH2:30][C:27]1[C:28]2[N:29]=[C:21]([C:12]3[N:11]([CH3:31])[C:10]([CH:5]([OH:4])[CH2:6][CH:7]([CH3:9])[CH3:8])=[N:14][C:13]=3[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:22][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: CC(C)CC(OC(=O)N(C)C)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Agent: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: CC(C)CC(O)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Example 104 but using 1-[5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl]-3-methylbutyl dimethylcarbamate (Intermediate 100) in place of [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](phenyl)methyl dimethylcarbamate (Intermediate 97). Colourless solid (5 mg, 63%);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 16.22 g (0.1 mol) of 5-nitroindole, 35 g (0.205 mol) of 1-(2-chloroethyl)pyrrolidine hydrochloride, and 51 g (0.369 mol) of potassium carbonate in 500 mL of DMF is stirred for 48 hours at ambient temperature and then filtered. The filtrate is evaporated down, the residue dissolved in dichloromethane and dried over sodium sulfate. The desiccant is filtered off and the filtrate is evaporated down. Yield: 25 g (96.3% of theory); C14H17N3O2 (M=259.31); calc.: molecular ion peak (M+H)+: 260; found: molecular ion peak (M+H)+: 260; Rf value: 0.65 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F

Procedure:
A 2,6-difluoroaniline (4) is reacted with bromine in chloroform to yield 4-bromo-2,6-difluoroaniline (5).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C(F)(F)F)c2)CCCC1=O
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 3-(trifluoromethyl)benzyl chloride (1.53 g, 6.0 mM) and sodium iodide (900 mg, 6.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.02 g (63%) of the 9-[(3-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.6 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 7.0 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1727 and 1652. MS (ES) m/e 400, 402.