Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]O)[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2]
Reactant: OCc1cccnc1
Reactant: CCOCc1nc2c(c3cc(O)ccc3n3nnnc23)n1CC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2c(c3cc(OCc4cccnc4)ccc3n3nnnc23)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
5-(Ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-ol (260 mg, 0.76 mmol), was stirred in 10 mL of tetrahydrofuran (THF), 3-pyridylcarbinol (87 mg, 0.80 mmol), and triphenylphosphine (299 mg, 1.14 mmol). Diisopropyl azodicarboxylate (231 mg, 1.14 mmol) was added dropwise to the mixture. After 30 minutes, 2 additional drops of 3-pyridylcarbinol were added and the reaction was stirred overnight at ambient temperature. Analysis by thin layer chromatography indicated that a small amount of starting material still remained. Additional amounts of the reagents were added until all of the starting material was consumed. The reaction was filtered through an acidic ion exchange resin and the resin was washed with methanol, followed by 1M ammonia in methanol. The filtrate was concentrated under reduced pressure to provide 280 mg of 5-(ethoxymethyl)-6-(2-methylpropyl)-8-(pyridin-3-ylmethoxy)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinoline as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][Br:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Br)c(CBr)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
4-Bromo-3-methyl-benzoic acid ethyl ester (18.24 g, 75.4 mmol), N-bromosuccinimide (14.1 g, 79.2 mmol), and benzoyl peroxide (0.9 g, 3.77 mmol) were combined in CCl4, and the reaction was heated to 80° C. and stirred with a halogen desk lamp shining on it for 6 hours. The mixture was concentrated and partitioned between CH2Cl2 and H2O. The organic layer was separated and washed with H2O and brine, and then dried and concentrated. The residue was triturated with hexane (3×50 mL) and dried to give the title compound.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][C@@H:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:8][C:7]=2[CH:31]=1.[Br:32]N1C(=O)CCC1=O>CO.O>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([Br:32])[C:6]2[N:12]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][C@@H:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:8][C:7]=2[CH:31]=1
Reactant: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2cccnc2)C[C@H]1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1Cc2cc(Br)cc(Br)c2N(Cc2cccnc2)C[C@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a stirred solution of the compound (200 mg) of Example 16 in methanol and water (7.5 mL/0.5 mL), was added N-bromosuccinimide (73 mg). The mixture was allowed to stir for 1 h, and solvent was removed. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to give a solid (90 mg, 35%). (M+H): 564.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:43]([O:44][CH3:45])=[CH:42][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:43]([O:44][CH3:45])=[CH:42][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 18 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product isolated as an off-white foam (20 mg, 18%). mp: 170° C. (glass 105), MS (ESI+): 642.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 8.57 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=9 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1H), 5.32 (s, 1H), 3.89 (s, 3H), 3.72 (m, 2H), 3.68 (m, 2H), 3.30 (m, 3H), 2.88 (m, 2H), 2.74 (m, 2H), 2.70 (m, 2H), 2.66 (m, 2H), 2.46 (m, 2H), 2.42 (m, 2H), 2.34 (s, 3H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccsc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), thiophen-3-ylboronic acid (64 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 40-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (6.4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 6.61 (d, 1H) 7.63 (d, J=8.34 Hz, 2H) 7.84 (dd, J=5.18, 2.91 Hz, 1H) 7.93 (dd, J=5.18, 1.14 Hz, 1H) 8.04 (d, J=8.34 Hz, 2H) 8.23-8.40 (m, 2H) 9.12 (dd, J=3.03, 1.26 Hz, 1H) 11.24 (s, 1H). ESI-MS: m/z 379.2 (M+H)+.
Reaction SMILES: C([O:3]/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)C.O1CCOCC1.O.Cl>O1CCOCC1>[CH3:35][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:15]([C:12]2[N:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH:4]=[O:3])=[CH:7][C:8]3=[N:14][CH:13]=2)=[O:16])[N:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:21]=1
Reactant: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
A solution of (Z)-7-(2-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (82.8 mg, 0.177 mmol) in 1:1 dioxane/water (2 mL) was treated with 45 equivalents of 4.0 M hydrochloric acid in dioxane solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 1.5 hours, quenched with saturated aqueous sodium bicarbonate solution, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography on silica with a 10% MeOH in DCM solution as eluent to afford 37 mg of the impure desired product as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([CH2:23]O)[CH2:21][OH:22].Cl.CN(C)CCCN=C=NCC.N(C(C)C)(C(C)C)CC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][C:20]([CH2:21][OH:22])([N+:25]([O-:27])=[O:26])[CH2:19][OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc([C@H](C)C(=O)OCC(CO)(CO)[N+](=O)[O-])ccc2c1
Yield: 36.9 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g, 19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g, 25.4 mmol) and NEt(i-Pr)2 (11 mL, 63.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between 3N HCl (100 mL) and CH2Cl2 (200 mL×2). The combined organic layer was back washed with water and brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (gradient from 1:2 to 1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g, 39% yield). Mp 124-126° C. 1H NMR (300 MHz, 10% CD3OD/CDCl3) δ 7.73-7.64 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 3.9-3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, 10% CD3OD/CDCl3) δ 174.1, 157.4, 134.5, 133.5, 129.0, 128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.
Reaction SMILES: O[C@H:2]1[CH2:7][C@@H:6]([CH3:8])[S:5][C:4]2[S:9][CH:10]=[CH:11][C:3]1=2.[CH2:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[CH2:12]([N:14]([C@H:2]1[CH2:7][C@H:6]([CH3:8])[S:5][C:4]2[S:9][CH:10]=[CH:11][C:3]1=2)[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])[CH3:13]
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN([C@H]1C[C@H](C)Sc2sccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 2.5 °C
Yield: 43.9 %

Procedure:
Methylene chloride (130.5 mL), cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran (10.44 g), N-ethyl-2-nitrobenzene-sulfonamide (16.78 g) and triphenyl-phosphine (20.61 g) are mixed under nitrogen atmosphere. The mixture is cooled at 0-5° C. and diisopropyl azadicarboxylate (16.6 mL) is added, maintaining the temperature. The temperature is allowed to rise to 20-25° C. and is maintained until completing the transformation (2 hours). The resulting mixture is treated with 5% NaOH (100 mL). The resulting organic phase is vacuum distilled to dryness and the residue is chromatographed, obtaining 9.8 g of trans-4-[N-ethyl-N-(2-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)CC(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)CC(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 3,3,3-trifluoro-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=389.3 [M+H]+.
Reaction SMILES: C(=[N:14][CH:15]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]2[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]2)=[CH:23][CH:22]=1)[C:16]#[N:17])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[NH2:14][CH:15]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]2[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]2)=[CH:23][CH:22]=1)[C:16]#[N:17]
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(C#N)N=C(c3ccccc3)c3ccccc3)cc2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(N)C#N)cc2)O1
Temperature: 40 °C

Procedure:
To a solution of 2-(benzhydrylidene-amino)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]pentanenitrile (7.2 g, 15.5 mmol) in THF (50 ml) is added a 2M HCl (aq) (5 ml). The solution is heated at 40° C. for 4 hours and then allowed to cool to room temperature. The pH is adjusted to pH 9-10 using saturated aqueous sodium hydrogen carbonate solution and the organic solvent is removed in vacuo. The crude residue is dissolved in EtOAc (100 ml) and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified by chromatography on silica eluting with 5:1 to 1:1 iso-hexane/ethyl aEtOAc and 1% triethylamine to yield 2-Amino-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentanenitrile as a colourless oil which solidifies; 1H NMR (CDCl3): mixture of diastereoisomers 1.39 (3H, s), 1.43 (3H, s), 1.70-1.87 (4H, m), 2.60 (2H, tr, J=7.1 Hz), 3.62 (1H, br), 3.90 (2H, m), 4.00-4.18 (2H, m), 4.48 (1H, pent, J=6.9 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz). [M+H]+ 305
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([I:24])=[CH:19][N:18]=1.[Cl-].[Na+]>C(OCC)C.C(#N)C>[CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([CH3:11])[O:12][C:19]1[C:20]([I:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
8.55 g (47.4 mmol) of (2R,3R)-3-benzyloxybutan-2-ol in 56 ml of diethyl ether were admixed at 0° C. with stirring in portions with 2.07 g of sodium hydride (55%). After 10 minutes, the ice bath was removed and the mixture was stirred for a further 3 minutes at room temperature. The suspension formed was added at 0° C. to a solution of 6.52 g (23.7 mmol) of 2,4-dichloro-5-iodopyrimidine in 65 ml of acetonitrile. The mixture was stirred for 4 hours at 40° C. and then admixed with dilute sodium chloride solution. Extraction was carried out with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 4:1). This gave 4.12 g (9.8 mmol; yield: 41%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11](Cl)=[N:10][N:9]2[CH:15]=1)=[O:5])[CH3:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:10][N:9]2[CH:15]=1)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2nc(N3CCNCC3)ccc2n1

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1.000 g, 4.432 mmol), piperizine (0.458 g, 5.318 mmol) and potassium carbonate (0.620 g, 4.485 mmol) in 50 mL of toluene was refluxed for 48 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The crude product, 6-piperazin-1-ylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, obtained upon removal of solvent was used for next step reaction without further purification. Yield 1.016 g, 83%.
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[Li+]>C(O)C>[C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Dissolve 2,2-dicarboethoxy-indan (5.67 g, 21.7 mmol) in ethanol (150 mL). Add 1N lithium hydroxide (50 mL) and stir overnight at room temperature. Reflux for 1 hour and concentrate the solution in vacuo. Partition between ethyl acetate and 6N hydrochloric acid. Separate the organic phase and wash with brine. Dry (MgSO4) and evaporate the solvent i n vacuo to give an off-white solid. Distill (120°-160° C. @0 .2-0.5 mmHg) to give 2-carboxy-indan (2.5 g, 71%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for l5 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69 min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.075 g, 0.16 mmol) and, methanesulfonyl chloride (0.017 mL, 0.22 mmole) to give 41.6 mg of a light purple solid; Anal. (C24H27ClN4O3S×1.3H2O H, N, S.; M+425.4 Calcd 425.12.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:32][O:33][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].[Li+].CC([N-]C(C)C)C.[CH3:15][C:16]([S:19]([N:21]=[C:22]1[CH2:25][O:24][CH2:23]1)=[O:20])([CH3:18])[CH3:17]>C1COCC1>[C:16]([S:19]([NH:21][C:22]1([CH:2]([CH3:3])[C:1]([O:5][CH3:6])=[O:4])[CH2:25][O:24][CH2:23]1)=[O:20])([CH3:15])([CH3:17])[CH3:18]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Methyl propionate (2.71 g, 30.8 mmol) was dissolved in anhydrous THF (90 mL) and cooled to −78° C. under nitrogen. LDA (2M solution in THF, 15 mL, 30 mmol) was added drop-wise. After 1 hour at −78° C., a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Preparation 39, 1.35 g, 7.703 mmol) in anhydrous THF (10 mL) was added. The reaction was gradually warmed to room temperature and stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (1.276 g, 63% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:29][C:24]3[C:23]([N:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Solvent: CO
Product: O=c1[nH]c2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 396.0 mg of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 137.6 mg of 1,2-phenylenediamine is heated to 120° for 60 minutes. Thereafter, the mixture is suspended in methanol, filtered under suction and recrystallized from N,N-dimethylformamide/water. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p. >300 °.