Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:8][C@H:9]1[C@H:22]([OH:23])[C@@H:21]([CH2:24][OH:25])[O:20][C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]1[N:26]=[N+:27]=[N-:28])(=[O:7])[CH3:6].O.CCOC(C)=O>N1C(C)=CC(C)=CC=1C>[C:5]([O:8][C@H:9]1[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C:1](=[O:3])[CH3:2])[O:20][C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[C@@H:10]1[N:26]=[N+:27]=[N-:28])(=[O:7])[CH3:6]
Reactant: CC(=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1N=[N+]=[N-]
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)OC[C@H]1O[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1O
Temperature: -40 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Acetyl chloride (1.5 mL, 21.1 mmol) was added slowly to a solution of tert-butyldimethylsilyl 3-O-acetyl-2-azido-2-deoxy-β-D-glucopyranoside (7.25 g, 20 mmol) in 2,4,6-collidine (47 mL) under nitrogen at −40° C. After stirring at −40° C. overnight, water was added. The mixture was poured into EtOAc and extracted with 1 N HCl, brine and saturated NaHCO3. The organic phase was dried over Na2SO4, filtered and the solvents were removed in vacuo. Flash chromatography on silica gel (Hexanes:EtOAc 5:1→4:1) afforded 7 (7.59 g, 18.8 mmol, 94%) as a colorless solid. [α]24D: −31.6 (c 1.00, CH2Cl2); IR (thin film on NaCl) 3459, 2112, 1747, 1233, 1042, 841 cm−1; 1H-NMR (300 MHz, CDCl3) δ 4.81-4.74 (m, 1H), 4.62 (d, J=7.6 Hz, 1H), 4.37-4.31 (m, 2H), 3.75-3.46 (m, 2H), 3.53 (dd, J=7.7, 10.3 Hz, 1H), 3.13-3.09 (m, 1H), 2.18 (s, 3H), 2.10 (s, 3H), 0.94 (s, 9H), 0.17 (s, 6H); 13C-NMR (75 MHz, CDCl3) δ 171.8, 171.5, 97.2, 75.5, 74.3, 69.8, 66.0, 63.4, 25.8, 21.2, 21.1, 18.2, −4.2, −5.0; FAB MS (C16H29N3O7Si) m/z (M+) calcd 403.1775, obsd 403.1779.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)=[CH:4][CH:3]=1.C(O)(=O)C.Cl.[CH3:47][NH:48][CH3:49].C([BH3-])#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][O:31][C:32]2[CH:39]=[CH:38][CH:37]=[C:34]([CH2:35][N:48]([CH3:49])[CH3:47])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(C=O)c1)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(OCCOc2nc3c(c(=O)n(CCOC4CCCCO4)c(=O)n3C)n2Cc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of 3-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yloxy)ethoxy)benzaldehyde (100 mg, 0.171 mmol) in methanol (3 mL) and THF (3 mL) was added acetic acid (0.2 ml, 3.49 mmol) and dimethylamine hydrochloride (90 mg, 1.10 mmol). The mixture was stirred at room temperature for 1 h. Then the mixture was cooled to 0° C., sodium cyanoborohydride (16.1 mg, 0.256 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred and allowed to warm to room temperature overnight. The mixture was concentrated and purified via silica gel chromatography eluting with DCM/methanol (60:1) to give 7-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione (26.1 mg, 24.9%) as white solid. LCMS MH+ 613.
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[F:38][C:39]([F:51])([F:50])[C:40]([NH:42][C:43]1[CH:44]=[C:45]([OH:49])[CH:46]=[CH:47][CH:48]=1)=[O:41].B(F)(F)F.ClCCl>O1CCCC1>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[O:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([NH:42][C:40](=[O:41])[C:39]([F:50])([F:51])[F:38])[CH:44]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc(O)c1)C(F)(F)F
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OC[C@H]1O[C@@H](Oc2cccc(NC(=O)C(F)(F)F)c2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 25.8 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (500 mg, 0.99 mmol), 3-trifluoroacetamidophenol (407 mg, 1.98 mmol) from Stage 1 and boron trifluoride diethyletherate (1.41 g, 9.93 mmol, 1.25 ml) in a mixture of dry dichloromethane (10 ml) and dry tetrahydrofuran (30 ml) was stirred at room temperature under argon for 7 days. Work-up as in Stage 1 of Example 1 and purification by flash chromatography on silica gel (2% acetone in toluene as eluant) gave the title compound as a colourless solid (166 mg. 21%).
Reaction SMILES: CS([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)=O.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=1.CN(C=O)C>C(#N)C>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C:4]2[O:5][C:6]3[C:11]([C:12](=[O:15])[C:13]=2[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:23][CH:22]=1
Reactant: Cc1c(S(C)=O)oc2ccccc2c1=O
Reactant: NCc1ccc(CCCCO)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(NCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2-methanesulfinyl-3-methyl-chromen-4-one (0.35 g, 1.78 mmol) in acetonitrile (37 mL), 4-(4-aminomethyl-phenyl)-butan-1-ol (0.47 g, 2.13 mmol) and DMF (18 mL) were added. The reaction stirred in a 50° C. oil bath overnight under N2 atmosphere. The next day, the reaction mixture was cooled to room temperature and concentrated to yield an oil. Purification of the oil by flash column chromatography (100% ethyl acetate) afforded the desired product as a white solid (120 mg, 20% yield). 1H NMR (600 MHz, CDCl3): δ 8.20 (d, 1H, J=7.9 Hz), 7.53 (t, 1H, J=7.8 Hz), 7.35 (t, 1H, J=7.6 Hz), 7.31 (d, 1H, J=8.4 Hz), 7.29 (d, 2H, J=7.9 Hz), 7.21 (d, 2H, J=7.9 Hz), 4.82 (bt, 1H, J=5.9 Hz), 4.66 (d, 2H, J=5.6 Hz), 3.68 (m, 2H), 2.66 (t, 2H, J=7.5 Hz), 1.97 (s, 3H), 1.70 (m, 2H), 1.61 (m, 2H), 1.24 (bt, 1H, J=5.3 Hz); 13C NMR (150 MHz, CDCl3): δ 174.0, 160.3, 152.2, 141.4, 135.5, 130.7, 128.2, 126.9, 125.0, 123.8, 122.3, 115.8, 92.7, 61.5, 44.6, 34.8, 31.8, 27.2, 7.3.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid, followed by liters of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1050 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with diethyl ether to cause solidification. The solid was washed with diethyl ether five times and dried, to give 1350 mg of the title compound as a powder.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:31]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:31]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH2:40][CH2:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (1 g, 6.66 mmol) in anhydrous dichloromethane (5 mL) was added triethylamine (1.4 mL, 7.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g, 7.99 mmol), and 1-benzyl-piperidin-4-ylamine (1.26 mL, 6.66 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was triturated with methanol. The resulting solids were collected by filtration, washed methanol and dried under reduced pressure to afford N-(1-benzylpiperidin-4-yl)-4-formylbenzamide as a white solid (1.7 g, 80%). 1H NMR (DMSO, 300 MHz): δ 8.41 (s, 1H), 7.85 (d, 2H), 7.77 (d, 2H), 7.28 (m, 5H), 3.78 (m, 1H), 3.4 (m, 2H), 3.80 (m, 2H), 2.05 (m, 2H), 1.45-1.80 (m, 4H); LCMS (m/z): 324 (MH+).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37]([Cl:41])=[C:38]([NH2:40])[CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]>>[Cl:41][C:37]1[S:36][C:35]([S:32](=[O:34])(=[O:33])[NH:31][CH:28]([CH2:27][OH:26])[CH2:29][OH:30])=[CH:39][C:38]=1[NH:40][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according to general procedure II. Light yellow solid. MS (ISP) 624.2 [(M−H)−]; mp 241° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([O:12]C)=[O:11])=[O:4].O.[OH-].[Li+:17]>C1COCC1.C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([O-:12])=[O:11])=[O:4].[Li+:17]
Reactant: COC(=O)c1nnn(C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1nnn(C)c1C(=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of 1-methyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester (1 g, 5.025 mmol) in THF (20 mL) and ethanol (5 mL) was added at 0° C. a solution of lithium hydroxide monohydrate (169 mg, 4.02 mmol) in water (5 mL) over a period of 10 min. The reaction mixture was allowed to stir at 0° C. for 3 h. The mixture was diluted with water (10 mL) and washed with ethyl acetate (2×50 mL). The aqueous layer was evaporated under reduced pressure and the crude material thus obtained was dried by azeotropic distillation with toluene to afford the product as white solid (0.6 g, 3.24 mmol, 64.5%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[C:19]([O:23][C:24](=[O:33])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:19]([O:23][C:24](=[O:33])[NH:25][CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:2]2[C:3]3[N:4]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)=[CH:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:30][CH2:31]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Temperature: 95 °C
Reaction time: 15 h

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (0.9 g, 3.24 mmol) in DMF (25 mL) was added trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.04 g, 4.86 mmol) followed by diisopropylethylamine (0.63 g, 4.86 mmol). The reaction mixture was stirred at 95° C. for 15 hours and the mixture was poured into water. The precipitate formed was filtered, and. the obtained solid was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 1.23 g, 83.4%). LC-MS: [M+H]+ 456.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:23][C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:11]=2)=[CH:6][C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][N:3]=1
Reactant: Cc1cccc(N)c1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)O)c2)c1
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)Nc3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, 3-((2-amino-5-(methoxycarbonyl)pyridin-3-yl)ethynyl)benzoic acid and m-toluidine are converted to the title compound.
Reaction SMILES: C(OP([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:18][CH:19]([CH3:33])[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]([C:9]([CH3:15])=[C:21]([CH2:20][CH:19]([CH3:33])[CH3:18])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)CC(=O)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=C(CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Ethyl 2-(diethylphosphono)propanoate (23.9 g.) was added to dry toluene (250 mls.) containing 80% sodium hydride in mineral oil (3.0 g.) at room temperature. The resultant mixture was heated to 50°-60° C. for 5 minutes and then cooled to -30° to -40° C. To the cooled mixture was added benzyl 4-methyl-2-oxopentanoate (20 g.) and the resulting mixture was allowed to warm to room temperature over a period of 1 hour. The toluene solution was washed with dilute citric acid (50 mls.), water (2×50 mls.) and then dried over anhydrous sodium sulfate. The toluene was removed by evaporation in vacuo to yield E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)butenoate as a mixture of isomers in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[S:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C>C1COCC1.[Ni]>[S:20]1[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:17][CH2:16]2)=[N:19]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 96 %

Procedure:
3-{4-[2-(4-Nitro-phenyl)-ethyl]-piperazin-1-yl}-1,2-benzisothiazole (942 mg, 2.56 mmol) was dissolved in 50 mL of THF treated with triethylamine (0.3 mL) and with wet Raney nickel (0.14 g). The resulting mixture was placed on a shaker type hydrogenator, purged with hydrogen, pressurized (two re-pressurizations were needed to maintain the pressure between 3 and 17 psig) and shaken at room temperature for 64 hours. The resulting mixture was filtered to remove the catalyst then filtered a second time over celite before the filtrate was concentrated. The resultant white solid was dried in vacuo (830 mg, 2.45 mmol). Yield 96%; mp 154° C.; MS (APCI): 339 [M+H]+.
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[CH2:3][NH:2]1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])OC>CO>[CH3:15][O:11][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1](=[O:12])(=[O:13])[NH:2][CH:3]=1
Reactant: O=C1CNS(=O)(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC([O-])[O-]
Solvent: CO
Solvent: O
Product: COC1=CNS(=O)(=O)c2ccccc21
Yield: 375.1 %

Procedure:
A mixture of 1.97 g (10 mmol) of 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide, 500 mg (2.6 mmol) of p-toluenesulfonic acid monohydrate, 20 ml of methyl orthoformate and 20 ml of methanol was refluxed for 3 hours. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: methylene chloride:ethyl acetate=40:1), whereby 2.06 g of the title compound were obtained (yield: 97%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].C(O[CH:10]1[NH:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=O)C>C1COCC1>[CH2:3]([S:5][C@@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH3:4]
Reactant: CCS
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a 0° C. suspension of NaH (60% oil dispersion, 200 mg, 498 mmol) in THF (20 ml) was added ethanethiol (0.37 mL, 4.98 mmol). The resultant mixture was stirred for 10 min, cooled to -20° C., and compound 13 (1.9 g, 3.83 mmol) was added. The solution was stirred further for 30 min at room temperature and concentrated. The residue was partitioned between ethyl acetate and pH 7.0 aqueous buffer. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (Et2O) to afford 718 mg (36%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.Cl[CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22]>>[Cl-:11].[NH2:1][C:2]1[N:3]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N+:6]=1[CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22]
Reactant: ClCSc1ccccc1Br
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Product: Nc1n(CSc2ccccc2Br)c2cc(Cl)c(Cl)cc2[n+]1CSc1ccccc1Br
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,6-dichlorobenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-bromophenyl chloromethyl sulfide, the title compound is obtained.
Reaction SMILES: C(/[CH:4]=[CH:5]/[C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)(O)=O.C([O-])([O-])=O.[K+].[K+].[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[Br:28]/[CH:4]=[CH:5]/[C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)/C=C/c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1/C=C/Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89681.6 %

Procedure:
To a solution of (E)-5-(2-carboxyvinyl)-2′-deoxyuridine (5.777 g, 19.37 mmol) in dimethylforamide (29 mL) was added K2CO3 (5.890 g, 42.61 mmol) and the suspension stirred at room temperature for 15 mins. A solution of N-bromosuccinimide (3.655 g, 20.53 mmol) was added dropwise over 30 mins at 20° C. The resulting suspension was filtered and the solid washed with DMF. The combined filtrate and washings were evaporated to dryness in vacuo and the residue dissolved in MeOH. To this silica gel was added and the suspension evaporated to dryness and the solid applied to the top of chromatographic column. The column was eluted with chloroform/methanol 92/8 to give a white solid (5787 g, 71.9%). Crystallisation from water gave a white powder.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:20].O1CCOCC1>O1CCOCC1>[ClH:20].[CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of O1-tert-butyl O4-ethyl 4-methylpiperidine-1,4-dicarboxylate (1 g, 3.68 mmol) in 1,4-dioxane (10 mL) was added HCl-1,4-dioxane (4.0 M, 15 mL) solution. The mixture was stirred at rt for 30 minutes. After completion of reaction (by TLC), solvent was evaporated to obtain brown solid material (0.90 g) that was carried forward to the next step without purification. MS: 172.16 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:13][CH:14]=1>C1(C)C=CC=CC=1>[CH2:24]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(NC(=O)/C=C\C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Maleic anhydride (0.18 g, 1.8 mmol) was dissolved in toluene (2 mL). m-Aminophenyltributylstannane as described above (0.70 g, 1.8 mmol) in toluene (4 mL) was added dropwise over a 5 minute period. After the addition was complete, the reaction mixture was stirred for 15 minutes at room temperature then cooled in an ice-water bath. The precipitaed yellow product N-(m-tri-n-butylstannylphenyl)maleamic acid was collected by vacuum filtration, recrystallized from toluene and dried overnight in a vacuum dessicator (0.75 g, 85%): mp. 130°-131° C. 1H NMR (Me2SO-d6, δ); 10.4 (singlet, 1H, OH); 7.6 (singlet, 2H, aryl C2-H and aryl C6-H); 7.3 (triplet, 1H, aryl C5-H); 7.2 (doublet, 1H, aryl C4-H); 6.4 (doublet of doublets, 2H AB, J=12 Hz, 2 CHC=O); 0.9-1.6 (muliplets, 27H, 3× n-C4H9).