Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:20]1([CH2:19][O:18][CH2:17][CH:16]=[C:11]2[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=CCOCC1CC1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(COCC1CC1)=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
A reaction flask was charged with 3-(2-cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (138LH49) (0.115 g, 0.37 mmol) in DCM (2 mL). TFA (0.5 mL) was added and the reaction was stirred at rt for 3 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the crude title compound (0.090 g).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:26]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:35]4[N:36]=[C:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:33][C:34]=4[CH3:50])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.44-7.41 (m, 3H), 7.13 (d, 2H, J=8.79 Hz), 6.78 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.79 Hz), 6.41 (d, 1H, J=2.44 Hz), 6.32 (dd, 1H, J=8.79 Hz, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.17 (t, 2H, J=6.35 Hz), 3.15 (d, 1H, J=14.16 Hz), 3.04-3.00 (m, 3H), 2.38 (s, 3H), 1.30 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H28NO7 502.1866, found 502.1881.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][CH2:18][CH2:19]Br>CC#N>[CH3:16][O:17][CH2:18][CH2:19][O:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COCCBr
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1cccc(CO)c1
Temperature: 110 °C

Procedure:
A mixture of 10 g (80.6 mmol) of 3-(hydroxymethyl)phenol, 78.4 g (241.7 mmol) of Cs2CO3 and 8.4 mL (88.6 mmol) of bromoethyl methyl ether in 150 mL of CH3CN is heated for 12 hours at 110° C. After cooling to room temperature, the medium is filtered, concentrated under reduced pressure, taken up in 500 mL of DCM, washed with brine (2×100 mL) dried over Na2SO4, filtered and then concentrated under reduced pressure. 10.9 g of 3-(2-methoxyethoxy)phenyl]methanol are obtained in the form of a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][N:21]([CH3:29])[C:22](=[O:28])[CH2:23][O:24][CH2:25][C:26]#[CH:27]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:10]1[C:11]2[O:15][CH2:14][O:13][C:12]=2[C:16]([C:27]#[C:26][CH2:25][O:24][CH2:23][C:22]([N:21]([CH3:29])[CH3:20])=[O:28])=[CH:17][C:9]=1[Cl:8]
Reactant: C#CCOCC(=O)N(C)C
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)COCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Yield: 81.9 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.236 g), cuprous iodide (0.96 g) and diisopropylamine (0.47 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.500 g) and N,N-dimethyl-2-(prop-2-yn-1-yloxy)acetamide (0.474 g) in ethyl acetate (8 ml) cooled to −20° C. under a nitrogen atmosphere; the resultant mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite, ethyl acetate (12 ml) was then added and the resultant solution washed with saturated aqueous sodium bicarbonate (20 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml). The combined organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.428 g). NMR Spectrum: (CDCl3) 2.96 (s, 3H), 3.02 (s, 3H), 4.06 (s, 2H), 4.31 (s, 2H), 4.52 (s, 2H), 6.02 (s, 2H), 6.89 (s, 1H); Mass Spectrum: M+H+ 311 and 313.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][CH2:19]3)=[O:17])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=2)[C:3]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3N)CC2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 0.350 g (0.853 mmol) of 2-(3′-amino-5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-1-(4-methyl-[1,4]diazepan-1-yl)-ethanone in acetonitrile (50 mL) is added 0.15 g (0.853 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature during which time a solid precipitates from solution. The formed solid is collected by filtration, washed with cold diethyl ether and dried on the filter pad to provide 0.308 g (66.0%) of N-{5′-bromo-4-[2-(4-methyl-[1,4]diazepan-1-yl)-2-oxo-ethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-3-chloro-benzamide in N,N-dimethylformamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[O:21][C:22]4[C:27]([C:28](=[O:37])[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[O:21][C:22]4[C:27]([C:28](=[O:37])[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of example 54 (0.200 g, 0.383 mmoles) in dichloromethane (30 ml), BBr3 (1M in dichloromethane, 2.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.070 g, 36% yield). MP: 280-283° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.69(s,1H), 8.20(s,1H), 8.06(dd, J=8.2,1.7 Hz, 1H), 7.80(m,1H), 7.51(m,2H), 7.39(m,2H), 7.17(m, 2H), 7.11(dt, J=8.7,2.2 Hz, 1H), 7.02(d, J=8.6 Hz, 1H), 7.00(s,1H), 6.86 (dd, J=7.7,1.8 Hz, 1H), 5.53(s, 2H). Mass: 479.88(M+).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14](N)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.S(=O)(=O)(O)[OH:22]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]([OH:22])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1ccc2c(c1)CCc1ccccc1C2=O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of (5-oxo- 10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)acetamide (17.4 g.) in a mixture of concentrated sulphuric acid (d = 1.83; 70 cc.) and water (70 cc.) is heated with vigorous stirring for 3 hours at 100°C. After cooling, the product which precipitates is filtered off and then added to 2N sodium hydroxide solution (200 cc.). The alkaline solution is extracted with diethyl ether and then acidified by adding 2N sulphuric acid (250 cc.). The product which precipitates is filtered off, dried and then recrystallised from ethyl acetate (100 cc.) to give (5-oxo-10,11 -dihydrodibenzo[a,d]cyclohepten-2-yl)acetic acid (11.5 g.) melting at 154°C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:14]([O:15][Si](C(C)(C)C)(C)C)[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[C:29]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:46]4[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=4[F:53])[S:36][C:37]=3[NH:38]C(=O)OC(C)(C)C)=[O:32])=[CH:28][N:27]=[C:26]3[O:54][CH2:55][CH2:56][C:25]=23)[CH2:10]1)=O)(C)(C)C.[H+].[H+].F[Si-2](F)(F)(F)(F)F.O.[NH4+].[OH-]>CC#N>[NH2:38][C:37]1[S:36][C:35]([C:46]2[C:47]([F:53])=[CH:48][CH:49]=[CH:50][C:51]=2[F:52])=[N:34][C:33]=1[C:31]([NH:30][C:29]1[C:24]([N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([OH:15])[C@H:9]([NH2:8])[CH2:10]2)=[C:25]2[CH2:56][CH2:55][O:54][C:26]2=[N:27][CH:28]=1)=[O:32]
Reactant: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
To a solution of tert-butyl [4-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]amino}carbonyl)-2-(2,6-difluorophenyl)-1,3-thiazol-5-yl]carbamate (29.2 mg, 0.0357 mmol) in MeCN (2.0 mL) was added a 1.7 M dihydrogen hexafluorosilicate solution in water (0.5 mL, 0.8 mmol). The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was neutralized with a 14.8 M NH4OH solution in water (300 μL, 4.44 mmol), and was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (6.0 mg, 33%). LCMS calc. for C23H25F2N6O3S (M+H)+: m/z=503.2. found 503.2.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[C:13]([O-])(=[O:15])[CH3:14].[Na+].C(OC(=O)C)(=O)C.O>C(Cl)Cl>[C:13]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[CH2:9]1)(=[O:15])[CH3:14]
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2cc(O)ccc2C1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of 57.6 g of 1,2,3,4-tetrahydro-6-hydroxy-isoquinoline-hydrobromide, 22.6 g of anhydrous sodium acetate, and 76.6 g of acetic acid anhydride in 300 ml of methylene chloride is held at the boiling point for one hour under reflux. 300 ml of water are added thereto, the organic phase is separated, and the aqueous phase is extracted several times with methylene chloride. After evaporation of the methylene chloride extract, the residue is dissolved in dilute sodium hydroxide, stirred for 30 minutes on a boiling water bath, and the reaction product is precipitated by the introduction of carbon dioxide. The filtered substance is recrystallized from ethanol. 43.5 g of 2-acetyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline are obtained. m.p. = 135° - 136° C. (ethanol - diisopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[C:13]([N:17]([CH3:19])[CH3:18])(OC)[CH3:14]>>[CH3:18][N:17]([CH3:19])/[C:13](/[CH3:14])=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1ccc(C)cc1
Product: C/C(=C\C(=O)c1ccc(C)cc1)N(C)C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 1-(4-methylphenyl)ethanone (2.0 g, 15 mmol) in (1,1-dimethoxy-ethyl)-dimethylamine was heated to 120° C. and stirred overnight. The reaction mixture was cooled and concentrated to dryness. The residue was stirred with 25 mL hexane for 1 h and filtered. The solids were washed with hexane and then dried to give the title compound (1.8 g, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.37 (3H, s), 2.65 (3H, s), 3.07 (6H, s), 5.68 (1H, s), 7.19 (2H, d, J=7.6 Hz), 7.77 (2H, d, J=8.0 Hz). [M+H] Calc'd for C13H17NO, 204. Found, 204.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=C[CH:4]=1.CSC1C=CC(NC)=[N:27]C=1>>[CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:27][CH:4]=1
Reactant: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CNc1ccc(SC)cn1
Product: CSc1ccc(CN2C(=O)c3ccccc3C2=O)nc1

Procedure:
The title compound is prepared in analogy to preparation 6a, substituting 4-(methylthio)-benzylamine with (5-methylsulfanyl-pyridin-2-yl)-methylamine (preparation 16a). ESI mass spectrum: [M+H]+=285; r.t. HPLC: 0.51 min (X012_S01).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=O)=[C:11]3[CH2:10][S:9]2)[CH:3]=1.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.C>O1CCOCC1.C(#N)C.C(N(CC)CC)C>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:16]([C:15]2[CH:14]=[CH:13][N:12]3[C:11]=2[CH2:10][S:9][CH:8]3[C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[O:18])[CH:25]=1
Reactant: O=C(O)c1ccn2c1CSC2c1cccnc1
Reactant: Cc1ccnc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccnc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 23.2 %

Procedure:
The hydrochloride of the acid chloride derived from (+)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid (12 g) is added, at a temperature between 65° and 72° C., to a solution of 2-amino-4-methylpyridine (4.3 g) and triethylamine (8.1 g) in dioxane (300 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (500 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with a saturated aqueous sodium bicarbonate solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (13.3 g) is thereby obtained, which is dissolved in boiling acetonitrile (140 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 2 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (75 cc in total) add 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. (+)-N-(4-methyl-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.1 g) in the form of cream-coloured crystals, m.p. 174° C., is thereby obtained. ([α]D20 =+82°±0.9°; c=1.09; dimethylformamide).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC=Cc1c(N)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C

Procedure:
10.0 g (24.0 mmole) of {(2R)-7-nitro -8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate and 28.0 g (123 mmole) of stannous chloride dihydrate were combined and heated to 70° C. in ethyl acetate (250 mL) for 6 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into ice and was made basic with sodium bicarbonate. It was then extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude oil was then chromatographed on silica gel with 50% hexane/methylene chloride to remove impurities and the desired product was eluted with 0.5% methanol/CH2Cl2 to give 8.16 g (91%) of the (R)-enantiomer of the title compound as a yellow oil. For analytical purposes, 50 mg of the yellow oil was crystallized from ethanol with the addition of fumaric acid to give the fumarate of the title compound. MS (ESI) m/z 375 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)([Cl:17])=O.[ClH:19]>[N+](C)([O-])=O>[ClH:17].[Cl:19][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][Cl:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCN(CCO)Cc1ccccc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bis(2-hydroxyethyl)benzylamine (19.5 g 0.1 mol) in nitromethane (150 mL) cooled with a water/ice bath is added thionyl chloride (60 mL). The mixture is stirred at room temperature for 2 h, then at 80° C. for 1 h 30. After cooling again with a water/ice bath, diisopropyl oxyde (350 mL) is added, causing the hydrochloride to precipitate. This is filtrated, rinsed with diisopropyl oxide and dried to give bis(2-chloroethyl)benzylamine hydrochloride.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:32]=[C:33]1[NH:37][CH:36]([CH2:38][CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1>ClCCl.CN(C)C1C=CN=CC=1>[O:41]=[C:40]([NH:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:8])[CH2:39][CH2:38][CH:36]1[CH2:35][CH2:34][C:33](=[O:32])[NH:37]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.033 mol) L-alanine ethyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 5.42 ml (0.039 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, concentrated, and diluted with 60 ml of dichloromethane. A mixture of the following is added in a single addition: 4.84 g (0.025 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.08 g (0.02 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethane-methanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-alanine, ethyl ester with a melting point of 88°-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[C:10]([I:11])[C:4]=2[C:3]=1[CH:12]=[O:13].[OH-].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:9]=[C:10]([I:11])[C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: O=Cc1c(F)cnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(C=O)c(F)cnc32)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde in DMF (12 mL) was added NaOH (0.716 g, 17.91 mmol). The deep red solution was stirred for 30 min after which 4-methylbenzene-1-sulfonyl chloride (3.13 g, 16.42 mmol) was added. The reaction mixture was stirred for 2 h, subsequently diluted with EtOAc, and washed with water and brine. The extracts were dried over MgSO4 and concentrated. Purification by silica column chromatography (DCM, 100%) afforded the title compound as light yellow solid (3.65 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3 H) 7.45 (m, J=8.08 Hz, 2 H) 8.02 (m, J=8.34 Hz, 2H) 8.42 (s, 1 H) 8.59 (d, J=2.53 Hz, 1 H) 11.13 (s, 1 H). [M+H] calc'd for C15H10FIN2O3S, 445; found, 445.1.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26](CC=CN)[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:32])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(N(CC)CC)C>O.CN(C=O)C>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:32])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: NC=CCc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 mg of 5-(3-aminoallyl)-2′-deoxyuridine-5′-triphosphate, ammonium salt (Sigma Chemical) in 100 μL of water is added a solution of 3 mg of Compound 72 (Example 73) in 100 μL of DMF, followed by addition of 5 μL of triethylamine. After the mixture is stirred at room temperature for 3 hours, the solution is evaporated to dryness under vacuum and the residue is purified by chromatography over lipophilic SEPHADEX resin using water for elution. The first green fluorescent fractions are combined and lyophilized to give the fluorescent nucleotide conjugate as an orange solid (Compound 107) Alternatively a fluorescent conjugate (Compound 108) of deoxyuridine-5′-triphosphate is prepared using 5-(3-amino-1-propynyl)-2′-deoxyuridine-5′-triphosphate in place of 5-(3-aminoally)-2′-deoxyuridine-5′-triphosphate (as described in Hobbs, Jr. et al, supra).