Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:38])(=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[Na+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:38][C:27](=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCCCCCC(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 71.3 %

Procedure:
To 200 ml of acetone-water (1:1) are added 6.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 5.2 g of sodium n-decanoate and the mixture is refluxed for 10 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 300 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 750 ml of diisopropyl ether-n-hexane (1:9), elution is carried out with 1000 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 5.2 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=1.O>C(O)C>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:23][C:22]([C:18]1[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=1)=[O:24])[CH3:10]
Reactant: CC(=O)c1cc(C)ccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cc(C)ccn1
Reaction time: 0.17 h

Procedure:
Diethyl oxalate (4.42 mL) was added to sodium ethoxide (2.22 g) in ethanol (22 mL), and the mixture was stirred for 10 minutes. The above-obtained 1-(4-methyl-2-pyridyl)ethanone (2.20 g) in ethanol (22 mL) was added to the mixture, followed by stirring at room temperature for 20 minutes. Water was added to the reaction mixture, and the resultant mixture was washed with diethyl ether, and then the aqueous layer was partitioned by use of saturated aqueous ammonium chloride and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(4-methyl-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester as an oily product (2.84 g, 74%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([S:11]([F:14])(=[O:13])=[O:12])=[CH:5][C:6]=1[S:7]([F:10])(=[O:9])=[O:8].C1N2CN3CN(C2)C[N:16]1C3.S(=O)(=O)(O)O>CO>[NH2:16][C:2]1[S:3][C:4]([S:11]([F:14])(=[O:13])=[O:12])=[CH:5][C:6]=1[S:7]([F:10])(=[O:9])=[O:8]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=S(=O)(F)c1cc(S(=O)(=O)F)c(Cl)s1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1sc(S(=O)(=O)F)cc1S(=O)(=O)F
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-3,5-bisfluorosulphonylthiophene (8.5 g), hexamine (8.5 g) and methanol (90 ml) was stirred under reflux for one hour. The mixture was cooled to 25° C., poured into dilute sulphuric acid and extracted with ethyl acetate to give the product as an oil (6.3 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21](C2C=CC=CC=2)[NH2:22])[CH:18]=[CH:19][CH:20]=1.[C:29](Cl)(=[O:39])[O:30][C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1.O>N1C=CC=CC=1>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@@H:31]([O:30][C:29](=[O:39])[N:22]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]3[O:1][CH2:5][CH2:4][O:3]3)[CH:16]=1)[CH2:32]2
Reactant: NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Solvent: O
Solvent: c1ccncc1
Product: O=C(O[C@H]1CN2CCC1CC2)N(Cc1cccc(OCCCCCCCCC2OCCO2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154.1 %

Procedure:
To a stirred solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)-(phenyl)-methanamine (0.62 g, 1.62 mmol) in pyridine (10 mL) at 0° C., (R)-quinuclidin-3-yl carbonochloridate (0.48 g, 2.1 mmol) was added. The reaction was stirred at 0° C. for 1 hour and then allowed to warm to RT for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on a KP-NH Biotage cartridge eluting with 0-20% methanol in ethyl acetate to afford the title compound (0.67 g, 78%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Cn1c(Nc2ccccc2)nccc1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.104 g, 0.517 mmol) in CHCl3 (5 mL)/MeOH (1 mL) at 0° C. was added bromine (0.027 mL, 0.517 mmol). The reaction mixture was stirred for 30 minutes at room temperature and then quenched with 10% aqueous sodium bisulfite solution. The reaction mixture was partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.145 g; 100%) as a white solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.94 (s, 1H), 7.47 (m, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 280, 282 (M+1, Br pattern).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[CH3:17][C:18]([CH3:30])([CH3:29])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][NH2:28])=[N:25][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:17][C:18]([CH3:30])([CH3:29])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:5](=[O:6])[C:4]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][NH:28]2)=[N:25][CH:26]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
220 mg (1.0 mmol) of the compound from Example 2A are initially charged in 5 ml of ethanol. 260 mg (purity 75%, 1.0 mmol) of the compound from Example 19A and 38 mg (0.2 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, and the solid formed is filtered off, washed with tert-butyl methyl ether and dried under high vacuum. This gives 37 mg of the title compound. The mother liquor is put aside and used for preparing the hydrochloride (see Example 89).
Reaction SMILES: C([O:3][C:4](=[O:28])/[C:5](=[N:25]/[O:26][CH3:27])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH3:27][O:26]/[N:25]=[C:5](\[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)/[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)/C(=N/OC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CO/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 50 °C
Yield: 84.4 %

Procedure:
(Z)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid ethyl ester (0.2 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 3N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 50° C. for 30 minutes. After the solvents were removed in vacuo, the concentrate was diluted with water (10 mL), acidified with 1N hydrochloric acid (3 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The resulting solid was crystallized from dichloromethane-hexane to provide 0.157 g of (Z)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid as its hernihydrate, mp 118°-120° C.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=1)[CH2:24][C:23]2=[O:39]>>[N+:36]([C:32]1[CH:31]=[C:30]([CH:25]2[CH2:24][CH:23]([OH:39])[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=3)[O:26]2)[CH:35]=[CH:34][CH:33]=1)([O-:38])=[O:37]
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: O=[N+]([O-])c1cccc(C2CC(O)c3cc(O)ccc3O2)c1

Procedure:
2-(3-Nitrophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(3-nitrophenyl)chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (br s, 1H), 8.29 (s, 1H), 8.20 (dd, 1H, J 8.2, 2.3Hz), 7.93(d, 1H, J 7.9Hz), 7.71 (t, 1H, J 15.9, 7.9Hz), 6.89 (d, 1H, J 2.8 Hz), 6.66 (d, 1H, J 8.7 Hz), 6.57 (dd, 1H, J 8.7, 2.9 Hz), 5.47 (br s, 1H), 5.33 (d, 1H, J 10.7 Hz), 4.88-4.92 (m, 1H), 2.33-2.39 (m, 1H), 1.83-1.92 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[NH:2]1.CN(C)C=O.S(Cl)([Cl:18])=O>ClC1C=CC=CC=1>[Cl:18][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=c1[nH]sc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 75.6 g (0.5 mol) of 1,2-benzisothiazol-3-one, 54.8 g (0.75 mol) of N,N-dimethylformamide and 100.0 g of chlorobenzene. While stirring, 71.4 g (0.6 mol) of thionyl chloride was added dropwise thereto over 1 hour at 70° to 80° C., and the mixture was reacted at the same temperature for 8 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.93 kPa at 128° C. to give 75.1 g (0.45 mol) of 3-chloro-1,2-benzisothiazole. The yield based on the 1,2-benzisothiazol-3-one was 90%.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[N:21]1([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(O)C>[O:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C@H:2]([OH:1])[CH2:3][N:24]2[CH2:25][CH2:26][N:21]([C:27]3[N:28]=[CH:29][CH:30]=[CH:31][N:32]=3)[CH2:22][CH2:23]2)=[N:13]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 2-piperazin-1-yl-pyrimidine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=433.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:28][O:27]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[C@H:29]([CH2:31][OH:32])[CH2:28][O:27][C:26]4=[O:25])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)c(C)c1
Yield: 54.4 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (530 mg) described in Preparation Example 145 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (466 mg), the title compound (315 mg) was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CCNCC1
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(OC(C)=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 129.7 %

Procedure:
A mixture of 6-acetoxy-2-naphthoic acid (1 g, 4.34 mmol, 1.0 eq), methyl piperidine-4-carboxylate (684 mg, 4.78 mmol, 1.1 eq), HBTU (2.47 g, 6.51 mmol, 1.5 eq) and TEA (658 mg, 6.51 mmol, 1.5 eq) in DCM (20 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL). The combined organic layers were washed with water (100 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated to give methyl 1-(6-acetoxy-2-naphthoyl)piperidine-4-carboxylate as a yellow oil (2 g, yield: 100%). ESI-MS: 356.0 (M+H)+. 1HNMR (400 MHz, DMSO-d6) δ: 8.05 (d, 1H), 8.01-7.96 (m, 2H), 7.73 (s, 1H), 7.53-7.51 (m, 1H), 7.40-7.37 (m, 1H), 3.63 (s, 3H), 3.18-2.95 (m, 2H), 2.71-2.65 (m, 3H), 2.34 (s, 3H), 1.97-1.76 (m, 2H), 1.61-1.50 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]3[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]3=[N:23][CH:22]=2)[CH:2]=1.[OH-].[Na+].C=O.[BH3-][C:38]#N.[Na+].Cl>O=O>[NH2:31][C:29]1[N:28]=[C:27]([NH2:32])[C:25]2[CH:26]=[C:21]([CH2:20][N:19]([CH3:38])[C:3]3[CH:2]=[CH:1][C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=3)[CH:22]=[N:23][C:24]=2[N:30]=1
Reactant: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=O
Product: CN(Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 23 h

Procedure:
A suspension of compound II (R=H) (100 mg, 0.211 mmol) in O2 free water (5 ml) under N2 was adjusted to pH 6.4 with 1 N NaOH to give a solution which was treated with 38% HCHO (83.1 μl, 1.14 mmol) followed by NaBH3CN (19.9 mg, 0.317 mmol). The solution was maintained at pH 6.4 by gradual addition of 1 N HCl over a period of 45 minutes. The solution was stirred under N2 for 23 hours, filtered and acidified to pH 3.6 with 1 N HCl. The product was collected by filtration, washed with water at pH 3.6 and dried in vacuo (P2O5): yield 97 mg (94%), mp indefinite (softens and darkens above 217° C.); mass spectrum, m/e 454 (M+1)+ ;λmax nm (ε×10-3): 0.1 N HCl --221 (37.1), 311 (19.0); pH 7-219 (35.1), 247 (18.1), 305 (25.2); 0.1 N NaOH --249 (19.9), 305 (25.0), 355 sh (6.15); 1H-NMR (DMSO-d6, <5% w/v), δ2.00 m (CH2CH2CO), 2.28 t (CH2CO), 3.12 s (CH3), 4.32 m (CHN), 4.66 s (CH2N), 6.78 d, 7.72 d (C6H4), 8.31 d (5 --CH), 8.59 d (7 --CH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[N:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cc1cc(Cl)nc(SCC#N)n1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Nc2cc(C)nc(SCC#N)n2)cc1

Procedure:
A stirred mixture of 15.0 g. (0.075 mole) of (4-chloro-6methyl-2-pyrimidinylthio)aceto nitrile, 10.0g. (0.075 mole) p-anisidine and 7.5 g. (0.075 mole) of sodium carbonate in 150 ml of ethanol was heated under reflux for five hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The oily residue was dissolved in ethyl acetate. Dilution of the ethyl acetate solution with petroleum ether and cooling in ice yielded a precipitate. This solid was collected and recrystallized from a mixture of benzene-petroleum ether to afford 7.2 g. of product, m.p. 128°-131°.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH2:12][CH2:11][CH:10]([S:13](Cl)(=[O:15])=[O:14])[CH2:9]1>N1C=CC=CC=1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][S:13]([CH:10]1[CH2:11][CH2:12][O:8][CH2:9]1)(=[O:15])=[O:14]
Reactant: NCc1ccco1
Reactant: O=S(=O)(Cl)C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(NCc1ccco1)C1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a stirred solution of furfurylamine (0.171 g, 1.8 mmol) in pyridine (2 mL) at 0° C. was slowly added tetrahydrofuran-3-sulfonyl chloride (0.250 g, 1.5 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (0.220 g, 65%) as a thick oil. 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 6.36 (dd, 1H, J=3.3, 2.1 Hz), 6.31 (d, 1H, J=3.3 Hz), 4.68 (t, 1H, J=5.4 Hz), 4.36 (d, 2H, J=6.0 Hz), 4.05 (dd, 1H, J=10.2, 5.7 Hz), 4.02-3.78 (m, 3H), 3.65 (m, 1H), 2.36-2.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15]N(CC(NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.CCN(C(C)C)C(C)C.[CH2:48]([CH:55]1CCNCC1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[CH2:48]([CH:55]1[CH2:13][CH2:12][N:11]([C:6]2[C:5]([Br:26])=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCC(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 72 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (1.00 g, 3.96 mmol), DIPEA (3.5 eq, 13.86 mmol, 2.41 mL), isopropanol (20 mL) and 4-benzylpiperidine (1.1 eq, 4.36 mmol, 0.77 mL). Concentration in vacuo to half volume after 18 h gave a bright yellow solid, which was filtered and washed with cold water (2×5 mL) to give the product (1.12 g, 72%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.38 (qd, br, J=12.2, 3.5 Hz, 2H, 2× piperidine CHAHB), 1.60 (d, br, J=10.9 Hz, 2H, 2× piperidine CHAHB), 1.69-1.76 (m, 1H, piperidine CH), 2.55 (d, J=7.1 Hz, 2H, 2× piperidine NCHAHA), 2.74 (t, br, J=11.9 Hz, 2H, 2× piperidine NCHAHA), 3.22 (d, br, J=12.5 Hz, 2H, PhCH2), 6.93 (s, br, 2H, NH2), 7.16-7.18 (1H, m, phenyl H-4), 7.19 (d, J=7.4 Hz, 2H, phenyl H-2 & H-6), 7.28 (t, J=7.1 Hz, 2H, phenyl H-3 & H-5), 8.13 (s, 1H, pyridine H-6);
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:27])[C:9]([CH:11]1[CH2:13][C:12]1([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[OH-].[Na+]>CCOCC>[CH3:27][N:8]([CH2:9][CH:11]1[CH2:13][C:12]1([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:7]
Reactant: CN(C)C(=O)C1CC1(c1ccccc1)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)CC1CC1(c1ccccc1)c1cccc(Cl)c1

Procedure:
To a solution of lithium aluminum hydride (0.30 g) in ether (10 ml) was added a solution of 2-(m-chlorophenyl)-2-phenylcyclopropanecarboxylic acid N,N-dimethylamide (0.900 g) in ether (15 ml) under ice-cooling, and the resulting mixture was stirred under reflux for 3 hours. The reaction mixture was cooled, admixed with a 10 % aqueous solution of sodium hydroxide (20 ml) and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate and evaporated to afford N,N-dimethyl-2-(m-chlorophenyl)-2-phenylcyclopropylmethylamine as an oily substance. M.P. 188° - 190° C. (hydrochloride).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30].CO>>[NH2:30][C:17]1[C:18]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[C:12]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: N
Reactant: CSC[C@@H](O)[C@@H](CO)NCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Solvent: CO
Product: CSC[C@@H](O)[C@@H](CO)NCc1cn(COCc2ccccc2)c2c(N)ncnc12
Temperature: 25 °C
Yield: 60 %

Procedure:
The product from Example 6.7 (0.19 g, 0.435 mmol) was stirred in 7M NH3-MeOH (25 ml) for 24 h in a sealed tube at 135° C. (oil bath). After cooling to rt the solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-7M NH3-MeOH 96.5:3.5 then 95:5) to give (2R,3S)-2-((4-amino-5-(benzyloxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-4-(methylthio)butane-1,3-diol (0.108 g, 60%) as a yellow gum. 1H NMR (CD3OD) δ 8.17 (s, 1H), 7.46 (s, 1H), 7.28 (m, 5H), 5.63 (s, 2H), 4.57 (s, 2H), 4.07 (d, J=13.7 Hz, 1H), 3.91 (d, J=13.7 Hz, 1H), 3.81-3.73 (m, 2H), 3.64 (dd, J=11.4, 5.0 Hz, 1H), 2.81-2.69 (m, 2H), 2.54 (dd, J=13.5, 7.4 Hz, 1H), 2.04 (s, 3H). 13C NMR (CD3OD, referenced to the centre line of CD3OD at 49.0 ppm) δ 152.8, 151.5, 149.4, 137.8, 133.6, 129.5, 129.3, 129.2, 116.2, 115.1, 78.6, 71.4, 71.3, 62.1, 62.0, 42.0, 39.3, 16.0. +ESMS Found 418.1907 (M+H)+ C20H28N5O3S requires 418.1913.