Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][CH2:21][CH2:22][O:23][C:24](=[O:27])[CH2:25]Br)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CC(O)=O.[OH-].[Na+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][CH2:21][CH2:22][O:23][C:24](=[O:27])[CH2:25][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: C1COCCN1
Reactant: O=C(CBr)OCCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(CN1CCOCC1)OCCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of bromo-acetic acid 2-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-ylamino]-ethyl ester (35 mg, 0.082 mmol) in morpholine (1 ml) was stirred at room temperature for 1.5 hours. The mixture was poured into 2% AcOH aqueous solution (50 ml) with stirring. The mixture was then basified with NaOH solution. The solid was filtered, washed with water, dried under vacuum to give morpholin-4-yl-acetic acid 2-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-ylamino]-ethyl ester as a yellow solid (18 mg, 51%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Yield: 61 %

Procedure:
{(1R)-1-{N-Methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 ml) and dichioromethane (40 ml) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from dichioromethane (80 ml). The residue was crystallised from ethyl acetate to give 1.19 g of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:36]([NH2:38])[CH3:37]>>[CH2:36]([NH:38][CH:19]1[CH2:20][N:15]([C:13]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:14])[CH:16]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:17][CH2:18]1)[CH3:37]
Reactant: CCN
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Product: CCNC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2sc(C)nc2-c2ccccc2)C1

Procedure:
N-((5-(Ethylamino)-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and ethyl amine. (ESI) 514 (M+H).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][CH:8]=1)N.C(O)C.[H][H]>[Ni].O>[NH2:1][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: NNc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1

Procedure:
Alternatively, 5.0 g of 3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine, 100 ml of ethanol, 10 ml of water and Raney nickel catalyst was shaken with hydrogen under 40 pounds of pressure in a Parr apparatus for 18 hours. The mixture was cooled and filtered and the filtrate concentrated to a gummy soid which was crystallized from dichloromethane-hexane to give 3-amino-6-[3-(trifluoromethyl)phenyl]pyridazine as off-white crystals, mp 138°-139° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCc1ccccc1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (4.4 g, 31.2 mmol) in EtOH (32 mL) was added at 0° C., 2-phenylethanamine (4.11 mL, 32.8 mmol). Mixture went from light yellow to bright orange instantly and it was stirring overnight at RT. Another equivalent of 2-phenylethanamine was added (4.11 mL, 32.8 mmol) and the mixture was heated to 50° C. overnight. Water was added (20 ml) and the resulting orange solid was isolated by filtration to afford 6.99 g of 2-nitro-N-phenethylbenzenamine (Yield: 92%) as an orange crystalline solid.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:12](=O)[CH:11]=C1.C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[CH:11]1[C:12]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:21]=1[OH:23]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc2ccccc2c1

Procedure:
Following the procedure of Example 1 but using 0.506 g. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.327 g. of β-naphthol, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3) followed by ethyl acetate-hexane (7:3). The residue obtained by concentration of selected fractions, 0.45 g., is crystallized from ethyl acetate diluted with two volumes of hexane as the title compound, white free-flowing crystals, m.p. 49.0°-50.0° C., having Rf 0.5 (TLC on silica gel in ethyl acetate-hexane (1:1)).
Reaction SMILES: CS[C:3]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[N:4][CH2:5][CH3:6].[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1>C(#N)C>[CH2:8]1[C:9]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:10]=[N:11][N:7]1[C:3]([NH:4][CH2:5][CH3:6])=[N:28][S:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:16][CH:17]=[CH:18]2)(=[O:27])=[O:26]
Reactant: CCN=C(SC)N1CC2(C=N1)CCCC2
Reactant: NS(=O)(=O)c1ccc2[nH]ccc2c1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc2[nH]ccc2c1)N1CC2(C=N1)CCCC2
Yield: 0 %

Procedure:
100 mg (1 mol equiv.) N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester and 92.5 mg (1.05 mol equiv.) 1H-indole-5-sulfonic acid amide were added to 3 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:EtOAc=1:1) afforded 152 mg (87%) 1H-indole-5-sulfonic acid (2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.2 Hz, 3H), 1.59-1.79 (m, 8H), 3.43-3.51 (m, 2H), 3.79 (br.s., 2H), 6.63-6.65 (m, 1H), 6.76 (s, 1H), 6.99 (br.s., 1H), 7.30 (t, J=2.8 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.76 (dd, J=8.6, 1.8 Hz, 1H), 8.27 (br.s., 1H), 8.54 (br.s., 1H).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:5]=[CH:4][CH2:3][CH2:2][CH:1]([OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCBr
Reactant: C=CCCC=O
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)CCCCCC
Yield: 88.1 %

Procedure:
4-pentenal (8.4 g., 0.1 mol) was added dropwise to the Grignard reagent from magnesium turnings (2.88 g., 0.12 mol) and 1-bromohexane (19.8 g., 0.12 mol) in ether (120 ml). The reaction mixture was then refluxed for 2 hours cooled, and quenched with ammonium chloride solution. After layers were separated, ether solution was evaporated and the residue distilled to give 1-undecen-5-ol (15.0 g., 88% yield, b.p. 93°-96°/1.2 torr).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(N(CC)CC)C>C(O)(C)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1
Reactant: NCc1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Fc1ccc2nc(CNc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1
Yield: 70.5 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)methylamine hydrochloride (0.113 g, 0.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.19 g, 0.8 mmol), triethylamine (0.28 mL, 2 mmol) in isopropanol (2 mL) was heated to 80° C. in a sealed tube for 6 h. The reaction mixture was partitioned between DCM and water and the organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-3.5% MeOH in DCM) to afford the title compound as a colourless gum, (0.125 g, 70%). LCMS (Method B): RT 2.99 min [M+H]+ 444.19.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=O)([O-:3])=[O:2].O.[NH2:21][NH2:22]>C(O)C>[O:15]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]2[NH:22][N:21]=[C:6]([C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[N+:1]([O-:3])=[O:2])[C:8]1=2
Reactant: NN
Reactant: O=C1CCCC(=O)C1C(=O)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2[nH]nc(-c3ccccc3[N+](=O)[O-])c21
Yield: 44.9 %

Procedure:
3.2 g (12.2 mmol) of 2-nitrobenzoylcyclohexane-1,3-dione and 0.52 g (12.2 mmol) of hydrazine hydrate (80%) are refluxed for 4 hours in 120 ml of ethanol. The ethanol is subsequently distilled off under reduced pressure, and 80 ml of methanol are added. The solid which precipitates is filtered off with suction and dried in vacuo. 1.41 g (45% of theory) of 4,5,6,7-tetrahydro-4-oxo-3-(2-nitro-phenyl)-1H-indazole of the formula ##STR6## and of melting point 236° C. (decomp.) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[C:9]([CH3:13])=[N:8][C:5]2=[N:6][CH:7]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[C:9]([CH3:13])=[N:8][C:5]2=[N+:6]([CH2:15][CH2:14][CH2:20][S:17]([O-:19])(=[O:18])=[O:16])[CH:7]=1
Reactant: O=S1(=O)CCCO1
Reactant: CC1=Nc2ncc(Cl)cc2C1(C)C
Solvent: CCOC(C)=O
Product: CC1=Nc2c(cc(Cl)c[n+]2CCCS(=O)(=O)[O-])C1(C)C
Temperature: 65 °C
Reaction time: 8 h
Yield: 153.6 %

Procedure:
A mixture of 1 g of 5-chloro-2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine and 1.60 g of 1,3-propanesultone was heated at 65° C. for 2 h. Ethyl acetate (ca. 100 mL) was added and the resulting mixture was stirred at room temperature overnight to yield 2.50 g of the product.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][O:14][C:15]([C:17]1[S:21][N:20]=[C:19](O)[CH:18]=1)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:21][N:20]=[C:19]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc(O)ns1
Reactant: CCCCc1noc(C)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)OC)sn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of 3-butyl-5-methyl-4-isoxazolyl-methanol (367 mg, 2.2 mmol) in THF (10 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (345 mg, 2.2 mmol) and triphenylphosphine (622 mg, 2.4 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.04 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=9:1 to 0:1) afforded the title compound (518 mg, 77%) as a colourless liquid. MS: m/e=311.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6](N[C@@H]2CCN(C)C2)=[O:7])=[C:4]([F:18])[CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]1>>[NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: CCN1CCC(N)CC1
Reactant: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Product: CCN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 229, on a 5.77 mmol scale utilising 4-amino-1-ethylpiperidine (Fluorochem; 815 mg, 6.35 mmol), as an orange solid (1.23 g, 75%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[NH:20][C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:30])=[O:29])[CH2:9][CH2:8]1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[N:20]([CH3:33])[C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:29])=[O:30])[CH2:11][CH2:12]1
Reactant: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.028 mol of 2-(3-(4-(2-pyrimidinyl)-1-piperazinyl)propyl)-7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 150 ml of absolute DMF, and 0.028 mol of sodium hydride is added to the solution and the mixture is stirred at room temperature for 0.25 hour. Then 0.028 mol of methyl iodide is added and the mixture is stirred at 25° C. for a further 2 hours. The product is precipitated as crystals by dropwise addition of a total of 18 ml of water. It is purified by crystallisation from isopropanol.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:30]>>[NH2:30][C:24]1[N:23]=[C:22]([I:29])[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) was added 100 ml of liquid NH3 at −78° C. and the solution was allowed to stir for 6 hours. After which time it was allowed to come to r.t. overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to give 6.5 (80%), m.p. 143-145° C., r.f.=0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][CH2:11][O:12]1)[C:30](=[O:31])[CH2:29][Cl:28]
Reactant: O=C(Cl)CCl
Reactant: CCOC(CNCC1OCCCO1)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel eqiuipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:21][C:22]2[C:23]([NH2:31])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=CC=1>C(O)C.[OH-].[Na+].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[C:8]3=[N:31][C:23]4[CH:24]=[C:25]5[O:29][CH2:28][O:27][C:26]5=[CH:30][C:22]=4[CH:21]=[C:7]3[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2c(c1)Cc1cc3cc4c(cc3nc1-2)OCO4
Temperature: 100 °C
Yield: 134.9 %

Procedure:
To 5-methoxyindan-1-one (350 mg, 2 mmol) is added 6[[(4-methylphenyl)-imino]methyl]-1,3-benzodioxol-5-amine (512 mg, 1 mmol) in ethanol (4 mL) and 2N sodium hydroxide (1 mL). The reaction mixture is heated at reflux (about 100° C.) for 16 hrs. Upon cooling the reaction product is dissolved in methylene chloride (200 mL) and extracted with a saturated sodium chloride solution (200 mL). The organic layer is dried with a rotatory evaporator. The resulting residue is chromatographed on silica gel with 2:3 ethyl acetate/hexanes to yield 8-Methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (393 mg, 67.4% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][C:29]#[N:30])=[O:27])=[CH:21][CH:20]=3)[C:11]3S[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.O[O:32][S:33]([O-:35])=O.[K+].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:28][C:29]#[N:30])=[O:27])=[CH:23][CH:24]=3)[C:11]3[S:33](=[O:35])(=[O:32])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 18-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide (19 mg, 0.044 mmol, 1 eq.), oxone (55 mg, 0.18 mmol, 4 eq.), THF (3 ml) and water (3 ml). The clear solution was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was treated with sodium bicarbonate solution. Solid was collected by filtration and washed with water. After drying, the title compound was obtained as a white solid (11 mg, 53% yield). MW=467.93. 1H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.61 (t, J=4.8 Hz, 2H), 3.56 (s, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(OC)(O[CH3:18])(=O)=O>[OH-].[K+].O>[CH3:18][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
102 g of 3-hydroxy biphenyl are dissolved in a solution of 67.8 g of potassium hydroxide in 650 cc of water. 86.6 cc of dimethyl sulphate are added dropwise within 30 minutes while stirring, whereby the reaction mixture warms itself. The reaction mixture is then kept at 75° for a further 15 minutes. After 1 hour a further 33.6 g of potassium hydroxide in 45 cc of water are added dropwise, and subsequently 37.8 g of dimethyl sulphate are added dropwise at 65° within 15 minutes. The mixture is again kept at 75° for 1 hour. After cooling, the oily layer is separated and taken up in methylene chloride. Washing is effected once with 2 N sodium hydroxide and once with water. Extraction is again effected twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and concentrated. 3-methoxy biphenyl is obtained and is used for the next reaction step without purification.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(O)C>O>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Yield: 74.6 %

Procedure:
To a 250-ml round bottom flask was added a magnetic stir bar, 8-[ethoxymethylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one (1.98 grams, 8.05 mmol), 4-amino-N-(4-pyridinylmethyl)benzenesulfonamide (2.16 grams, 8.2 mmol) and 95% ethanol (80 ml). The round bottom reaction flask was fitted with a water cooled reflux condenser. The reaction vessel was placed in an oil bath at room temperature with stirring and the temperature of the oil bath was then raised to a gentle reflux and maintained at that temperature for approximately 36 hours. The reaction vessel was removed from the oil bath and the hot mixture was filtered with the solids being collected by suction filtration. The resultant solid was washed with excess 95% ethanol and collected by suction filtration. The solid was then dried under vacuum for two days at room temperature to yield 2.785 grams (74.7%) of the thiazolindolinone compound. MS (M+H)=464.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:10])[C:5]([O:7]CC)=[O:6]>O.CO>[CH3:10][C:4]([S:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)([CH3:3])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(C)Sc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Sc1ccncc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.7 grams NaOH in 5 ml of water was added dropwise to a solution of 8.79 grams of ethyl 2-methyl-2-(4-pyridinylthio)propionate in 15 ml methanol. The solution was stirred at room temperature overnight, and then concentrated in vacuo to remove methanol. Concentrated HCl was added to the sodium salt and the mixture triturated with isopropanol and heated on the steam bath. The mixture was then cooled and filtered to remove sodium chloride. The filtrate was concentrated in vacuo and the resulting gummy solid dissolved by adding hot isopropanol. The mixture was cooled and filtered to give the title compound. The filtrate upon concentration and cooling gave a further yield of the title compound. M.P. 190°-192° C.; 1NMR and IR were both in agreement for the titled compound.