Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (395 mg, 1.29 mmol) was added dropwise to a solution of Intermediate 24c (254 mg, 1.07 mmol) and Et3N (0.20 mL, 1.40 mmol) in DMF (3 mL) at RT under N2. The mixture was stirred for 1 h then Et3N (0.10 ml, 0.70 mmol) and triisopropylsilyl trifluoromethanesulfonate (200 mg, 0.65 mmol) were added sequentially, and the mixture stirred for 1 h. The solvent was evaporated, the residue applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left the title compound (339 mg, 80%). LCMS (Method 1): Rt 4.74 min, m/z 393 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH2:14][O:15]C(=O)C)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=1)=O.CC1C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>C1(C)C(CCO)=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:1]([CH2:2][C:3]2[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=2)[C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1
Reactant: CCCOc1ccc(C(=O)CCC(=O)c2ccccc2Cl)cc1
Reactant: CC(=O)OCCOc1ccc(CN)nc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1CCO
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc(-c2ccc(-c3ccccc3Cl)n2Cc2ccc(OCCO)c([N+](=O)[O-])n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
To a solution of 0.2 gm of acetic acid 2-(6-aminomethyl-2-nitropyridin-3-yloxy)-ethyl ester (0.8 mmol) in 3 mL of 5:1 toluene-ethanol was added 0.20 gm of 1-(2-chlorophenyl)-4-(4-propoxyphenyl)-butane-1,4-dione and 10 mg of p-TsOH. The reaction mixture stirred at 100° C. for 72 h. The reaction mixture was poured into 200 mL of CHCl3 and washed twice with water (100 mL), saturated brine, dried (Na2SO4), and the solvents removed under reduced pressure. The residue was purified by column chromatography using 4% methanol-chloroform as an eluent to give 100 mg (25% yield) of an oil. This was used without further purification or characterization.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.S(O[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1)(=O)(=O)C>O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:21][CH2:22]1)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Sodium hydride (300 mg of a 60% suspension) was added to a stirred solution of 4-methylphenylsulphonamide and the mixture stirred at room temperature until effervescence had ceased. N-benzyloxycarbonylpiperidine-4-methanol mesylate (1.09 g) was added and the mixture heated at 100° C. for 7 hours. After cooling to room temperature it was diluted with water (200 ml) and extracted with ether (4×40 ml); the extracts were combined, washed with water (2×) and brine, dried (MgSO4) and evaporated to yield N-(1-benzyloxycarbonylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide; NMR (d6DMSO) δ 0.81-1.1(2H,m); 1.5-1.7(3H,m); 2.35(3H,s); 2.6(2H,t); 2.7-2.9(2H,m); 4.0(2H,d); 5.0(2H,s); 7.2-7.5(7H,m); 7.55(1H,t); 7.7(2H,d); m/e 403 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>C(#N)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Br
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 3.4 ml (24.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.82 g (12.1 mmol) of trans-2-aminocyclohexanol hydrochloride. After 16 hours at room temperature the batch is filtrated and the filtrate is concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1). 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: Cc1csc(CCC2(C(C)C)CC(O)=CC(=O)O2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(CCC2(C(C)C)CC(O)=C(Sc3cc(C)c(CO)cc3C(C)(C)C)C(=O)O2)n1

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-6; 0.33 g, 1.2 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2, 0.51 g, 1.4 mmol), potassium carbonate (0.48 g, 3.5 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 98-100° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]([NH:31][NH2:32])=O)[CH:26]=[CH:25][C:23]=2[N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOP(O)N(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O.CCOC(C)=O.CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]3[O:9][C:7]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)=[N:32][N:31]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cc1
Reaction time: 6 h
Yield: 41 %

Procedure:
Combine 4-cyano-benzoic acid (120 mg, 0.817 mmol), 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol), HATU (445 mg, 1.17 mmol), EDIPA (204 uL, 1.17 mmol), and DMF (5 mL) and stir for 25 hr. Dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Take the concentrate up in DMF (3 mL) and add Burgess reagent (555 mg, 2.33 mmol). Heat the reaction to 150° C. for 20 min by microwave irradiation. Dilute the reaction with EtOAc (75 mL) and extract with water (20 mL). Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the concentrate by silica gel chromatography (10-40% ACN/DCM) to afford a white solid. Suspend the solid in water and stir for 6 hr. Collect the solid by filtration and wash with Et2O. Dry the solid under vacuum at 40° C. for 2 days to afford the title compound (138 mg) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.63-7.68 (m, 1H) 7.70-7.74 (m, 2H) 7.79-7.85 (tautomer, m, 1H) 7.96 (tautomer, d, J=8.59 Hz, 1H) 8.06-8.15 (m, 3H) 8.35-8.40 (m+tautomer, 2H) 8.52-8.60 (m, 1H) 13.39 (d, J=12.76 Hz, 1H); LCMS tR=1.35 min, MS (m/z) 432.0.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:33])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][CH:24]=5)[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([OH:34])=[S:33])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][CH:24]=5)[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc(-c4ccc(C(=O)O)cc4)cs3)CS[C@H]12
Agent: [K]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(O)=S)=C(c3nc(-c4ccc(C(=O)O)cc4)cs3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
To a mixture of potassium benzhydryl 7β-(2-phenylacetamido)-3-[4-(4-carboxyphenyl)thiazol-2-yl]thio-3-cephem-4-carboxylate (450 mg), anisole (0.45 ml) and dichloromethane (1.35 ml) was added trifluoroacetic acid (0.9 ml) at 15° C. After stirring at room temperature for 1.5 hours, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran (10 ml) and water (15 ml), and the solution was adjusted to pH 7.2 with an aqueous sodium hydrogen carbonate. The separated aqueous solution was adjusted to pH 3.0 with 1N-hydrochloric acid and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the resulting powder was collected by filtration and dried in vacuo to give 7β-(2-phenylacetamido)-3-[4-(4-carboxyphenyl)thiazol-2-yl]thio-3-cephem-4-carboxylic acid (75 mg).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[C:7]2([CH2:12][CH2:11][N:10](CCCCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:9][CH2:8]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[C:54](=[O:55])[C:53]2[CH:56]=[CH:57][CH:58]=[C:51]3[C:52]=2[C:47](=[CH:48][CH:49]=[CH:50]3)[C:46]1=[O:59].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:2]=[C:3]1[C:7]2([CH2:8][CH2:9][N:10]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][CH:58]=[C:51]5[C:52]=4[C:47](=[CH:48][CH:49]=[CH:50]5)[C:46]3=[O:59])[CH2:11][CH2:12]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
Following the procedure of part (b) of example 26 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([N:6]([C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:22]
Reactant: COc1ccc(Nc2ccc(F)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N-(4-methoxyphenyl)aniline (1c) (90.78 g, 0.418 mol) and 3-fluoro-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) were mixed together and dissolved in anhydrous THF (200 mL) in a dry 1 L three-necked round-bottomed flask fitted with a stirring bar, a reflux condenser and an argon inlet. Anhydrous pyridine (132.22 g, 1.672 mol) was added via a syringe at room temperature under argon. The reaction mixture was stirred and heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered to remove pyridine salt. The solution was concentrated to remove THF solvent. The residue oil was washed with 200 mL of 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with a saturated aqueous Na2CO3 solution (150 mL) to remove excess benzoyl chloride and acid, dried over MgSO4 (50 g), filtered, and concentrated under reduced pressure to give an oil. The residue was purified by flash column chromatography using silica-gel with CH2Cl2/acetone (50/1 v/v) to afford the pure corresponding benzamide compound as a yellow solid. M.p. 54-56° C. MS (ESI) m/z 370.1 [M+H]+, 1H NMR (CDCl3/TMS) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CS(O)(=O)=O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:11][CH2:12][CH:13]2[C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CCC(O)c2c[nH]cn2)cc1
Agent: CS(=O)(=O)O
Product: CC(C)(C)c1ccc2c(c1)C(c1c[nH]cn1)CC2
Temperature: 60 °C

Procedure:
A mixture of 3-(4-tert-butylphenyl)-1-(1H-imidazol4-yl)-propan-1-ol (2.0 g) and methanesulfonic acid (30 ml) is heated at 60° C. for 5 minutes. The reaction is then quenched by pouring it into ice-water solution. The acidic solution is made basic with ammmonium hydroxide solution, and extracted with ethyl acetate. The combined organic layers are washed with water, dried with sodium sulfate, and evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography by eluting with methylene chloride-methanol as eluent. The product is crystallized from ethyl acetate. The yield is 220 mg.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[CH:21]([F:23])[F:22]>O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[F:22][CH:21]([F:23])[O:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sccc1O
Reactant: FC(F)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1sccc1OC(F)F
Temperature: 90 °C
Yield: 31.3 %

Procedure:
At room temperature, a mixture of 10 g (0.063 mol) of methyl 3-hydroxy-thiophene-2-carboxylate and 90 ml of toluene is admixed with a solution of 5.1 g (0.127 mol) of sodium hydroxide in 8 ml of water. The reaction mixture is heated with stirring to 90° C., 1.1 g of tetrabutyl-phosphonium bromide are added and 16.4 g (0.189 mol) of chlorodifluoromethane are introduced over a period of 30 minutes. The mixture is then stirred at 90° C. for one hour. The reaction mixture is subsequently cooled to room temperature and admixed with water. The organic phase is separated off, dried over sodium sulphate and then concentrated under reduced pressure at 50° C. The residue that remains is chromatographed over silica gel using cyclohexane:ethyl acetate=3:1 as mobile phase. Concentration of the eluate gives 4.1 g (31.3% of theory) of methyl 3-difluoromethoxy-thiophene-2-carboxylate in the form of an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[C@H:13]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([NH2:16])[C@H:13]([N:19]2[C:23]3[N:24]=[C:25]([NH2:29])[NH:26][C:27](=[O:28])[C:22]=3[S:21][C:20]2=[O:30])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)C[C@H]2N)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of compound [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-azido-tetrahydrofuran-2-yl]methyl benzoate (compound 33b, 200 mg, 0.466 mmoL) and triphenylphosphine (364 mg, 1.39 mmoL) in THF (10 mL) was added water (0.5 mL) at room temperature. After being stirred at 80° C. for 1 hour, the reaction was filtered and the filtrate was concentrated in vacuo to afford 80 mg crude product of [(2S,4R,5R)-4-amino-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl benzoate (compound 33c), which was used in next step directly. MS obsd. (ESI+) [(M+H)+]: 404.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[C:19]([CH3:27])=[CH:20][C:21]2[N:22]([CH:24]=[CH:25][N:26]=2)[N:23]=1.O>O1CCCC1.CN(C)C=O>[CH3:27][C:19]1[C:18]([O:16][CH2:15][CH2:14][CH2:13][S:10]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]2)(=[O:12])=[O:11])=[N:23][N:22]2[CH:24]=[CH:25][N:26]=[C:21]2[CH:20]=1
Reactant: Cc1cc2nccn2nc1Cl
Reactant: CN1CCN(S(=O)(=O)CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2nccn2nc1OCCCS(=O)(=O)N1CCN(C)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
In 20 ml of tetrahydrofuran-dimethylformamide (3:1) was suspended 110 mg of60% sodium hydride in oil followed by addition of 611 mg of 3-(1-methyl-4-piperazinylsulfonyl)-1-propanol and the mixture was stirred under nitrogen at room temperature for 30 minutes and at 50° C. for30 minutes. Then, 420 mg of 6-chloro-7-methylimidazo[1,2-b]pyridazine was added and the mixture was further stirred at 50° C. for 1 hour and at 70° C. for 1 hour. Following addition of 100 ml of iced water, the reaction mixture was extracted with ethylacetate (100 ml ). The extract was washed with 50 ml of saturated saline and dried over anhydrousmagnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethanemethanol (50:3). The fraction containing the desired product were pooled and concentrated. The residue was recrystallized dichloromethane-isopropyl ether to obtain 447 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH2:11])[CH2:3]1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].CCN(C(C)C)C(C)C>C1COCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:11][C@@H:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:12])([CH3:1])[CH2:3]2)[N:16]=1
Reactant: CC1(C)C[C@H](N)c2ccccc21
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(Cl)nc(Cl)n2)c2ccccc21
Reaction time: 1.5 h
Yield: 59.4 %

Procedure:
To a solution of (1S)-3,3-dimethylindan-1-amine (0.67 g, 4.2 mmol) in THF (3 mL) cooled to 0° C. was added cyanuric chloride (0.874 g, 4.74 mmol) resulting in a white solid. DIPEA (0.724 mL, 4.16 mmol) was added and the yellow mixture was stirred for 1.5 hours. The reaction was quenched with H2O and extracted with DCM (3×). The combined organic layers were dried (Na2SO4), filtered and collected in vacuo to give a pale yellow oil. The residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to afford the title compound (0.771 g, 60%) as a white solid. LC/MS: Rt=2.20 min, ES+ 310 (FA standard).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].C(O)C.[Na].[CH3:16][SH:17]>CCOCC.O>[CH3:16][S:17][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11]
Reactant: CS
Reactant: O=C1c2ccccc2CC1Br
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CSC1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
After 10 g of 2-bromo-1-indanone was dissolved into 50 ml of ethanol, 25 ml of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After stirring for 3 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. After 200 ml of ether was added thereto for extracting an organic phase, the ether layer was sequentially washed with an aqueous sodium chloride solution and water. After the ether layer was dried with magnesium sulfate, the ether was evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=7/1) to provide 3.2 g of 2-(methylthio)-1-indanone (yield: 38%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1([OH:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.[CH:30]1([NH:36][S:37]([OH:40])(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[CH:30]1([NH:36][S:37](=[O:38])(=[O:39])[OH:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[C:19]([O:17][C:5]1([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:21])[CH3:20]
Reactant: CN(C)CCC1(O)CCCCC1c1ccccc1
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC1(CCN(C)C)CCCCC1c1ccccc1

Procedure:
The procedure of Example I (c) is followed using 7.5 g of 1-(2-Dimethylaminoethyl)-2-phenylcyclohexanol (Example XIV) and 8 ml of acetyl chloride with 18 ml triethylamine giving 11.8 g crude acetate which is treated with 12 g cyclohexanesulfamic acid in tetrahydrofuran to give 6.7 g pure product, m. 140°-1°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Si]([C:18]#[N:19])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C1C=CC=CC=1>[C:18]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1)#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc2c1CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c1CCC=C2C#N
Temperature: 25 °C

Procedure:
A solution of 5-methoxy-1-tetralone (52.0 g, 0.29 mole, Aldrich), TMSCN (51 mL, 0.38 mole, Aldrich), 40 mL dry benzene, and catalytic AlCl3 was stirred under N2 at 65° C. for 1 hour. The reaction mixture was cooled and evaporated to dryness. To the residue was added 300 mL pyridine and POCl3 (80 mL, 0.88 mole). The reaction mixture was stirred at reflux for 2 hours, then was cooled to room temperature and was poured onto ice/concentrated HCl. A precipitate was collected, washed with water, and purified by column chromatography (silica gel/CH2Cl2) to obtain 54 g (73%); M+ 185.