Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)=[C:14]([NH2:15])[C:9]2=[C:8]([CH3:22])[C:7]=1[Cl:23].[H-].C([Al+]CC(C)C)C(C)C.CCOC(C)=O.CCCCCC>C1COCC1>[CH:18]1([NH:17][C:16]([C:13]2[S:12][C:10]3=[N:11][C:6]([O:5][CH2:4][CH2:3][OH:2])=[C:7]([Cl:23])[C:8]([CH3:22])=[C:9]3[C:14]=2[NH2:15])=[O:21])[CH2:20][CH2:19]1
Reactant: COC(=O)COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(OCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid methylester (0.250 g, 0.676 mmol) in THF (3 ml) at −78° C. is added dropwise a solution of diisobutylaluminum hydride (1.5M in toluene)(1.35 ml, 2.03 mmol). The reaction solution is stirred at −78° C. for 30 minutes, then room temperature for 1 hour. If the reaction is not complete, according to TLC (2:1 EtOAc:hexane), an additional 1.0 eq of diisobutylaluminum hydride (1.5M in toluene)(0.45 ml, 0.676 mmol) may be added. After 15 minutes, the reaction is quenched by the addition of 3 ml of a 1:1 mixture of MeOH:water. The reaction mixture is partitioned between water and EtOAc (50 ml each), and the layers are shaken and separated. The aqueous layer is extracted with 2×50 ml of EtOAc, and the combined organic layers are dried (anhydrous magnesium sulfate), filtered, and concentrated to give a yellow solid. This solid is taken up in 2:1 EtOAc:hexane, and once dissolved, a yellow precipitate is formed. The yellow solid is collected by filtration and dried in the vacuum oven at 60° C. overnight to afford the title compound as a yellow solid (0.155 g, 67%). Mass (m/z): 342.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1>C(OCC)(=O)C#C>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:2]=[CH:3][C:4]1=[O:8]
Reactant: NC1=CC(=O)CCC1
Agent: C#CC(=O)OCC
Product: O=C1CCCc2[nH]c(=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a 500 mL flask, added 3-amino-cyclohex-2-enone (110 g, 0.99 moL) and ethyl propiolate (100 mL, 0.99 moL) and attached a condenser. The mixture was heated to 100 degree Celsius. The reaction started slowly at beginning and accelerated as the reaction progress. After the reaction was refluxed at 120 degree Celsius for 4 h, the mixture was heated up to 150 degree Celsius to remove any liquid. Finally, the mixture was heated up to 190 degree Celsius and remained for 1 h. The reaction was cooled to room temperature and 300 mL methylene chloride was added. The mixture was trituated and filtered to give the desired product (34 g, 21%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]1[C:11]2([O:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25][C:26]4[NH:30][C:29]5[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=5[N:27]=4)[C:19]=3[CH3:35])[CH2:13][O:12]2)[CH2:10][CH2:9]1.ClC1C=CC=C(C(OO)=[O:44])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO.CO>[CH2:10]1[C:11]2([O:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25]([C:26]4[NH:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[O:44])[C:19]=3[CH3:35])[CH2:13][O:12]2)[CH2:8][CH2:9]1
Reactant: Cc1c(OC2COC3(CCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OC2COC3(CCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a toluene (30 ml)/methanol (3 ml) solution of the 2-(((4-(5,9-dioxaspiro[3.5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (290 mg, 0.73 mmol) obtained in the step (9h), a toluene/methanol (10:1) solution of 3-chloroperbenzoic acid (174 mg, 0.65 mmol as the content was regarded as 65%) was added at −70° C. in a nitrogen atmosphere. After the mixture was stirred at −50° C. for one hour, a saturated aqueous solution of sodium hydrogen carbonate was added. After the mixture was warmed to room temperature, the mixture was extracted with ethyl acetate twice. Organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate, ethyl acetate/methanol=9/1). Fractions containing the title compound was collected by use of ethyl acetate and concentrated. After diethyl ether was added to the residue, the solvent was distilled off to obtain the title compound (230 mg, yield: 76.2%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 60 °C
Yield: 58 %

Procedure:
10.8 g piperazine-1-carboxylic acid tert-butyl ester was added to 8.3 g 4-chloro-6-methoxy-pyrimidine and 16 mL triethylamine in 40 mL DMF. The reaction was stirred over night at 60° C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and evaporated. The residue was purified chromatography on silica gel (petrolether/ethyl acetate: 8/2) to yield 9.8 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(Cl)Cl.Cl[Si](C)(C)C>C(OC(=O)C)C>[C:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1)([CH:10]=[CH2:9])=[O:12]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-(4-aminophenyl)butyric acid (6 g, 3.36 mmol) was added to a 200 mL three-mouthed round flask, and methylene chloride (100 mL) was added and dissolved under the nitrogen atmosphere at 40° C. To the solution was added chlorotrimethyl silane (6.0 mL). The solution was refluxed and agitated for 2 hours and, after reaction, cooled down to the room temperature. While kept at 0 to 5° C. on an ice bath under the nitrogen atmosphere, an acid eliminator (in an excess amount by 10% in concentration relative to the reactant) was added dropwise through a funnel for 10 minutes, where the acid eliminator contained imidazole and tetraethyl amine mixed at the same mole fraction. In the same manner, a solution containing acryloyl chloride (2.8 mL) in methylene chloride (30 mL) was added dropwise for 20 minutes, and the solution was kept for 30 minutes of reaction and then warmed up to the room temperature for 2 more hours of reaction. After the solvent was removed, 2M sodium hydroxide solution (200 mL) was added, and the solution was stirred for 2 hours. The aqueous solution was weak-acidified (pH 5-6) with a 2M hydrogen chloride solution to form an aqueous solution containing a white precipitate. This solution was added to a separatory funnel along with ethylacetate (200 mL) and shaken up to cause phase separation into aqueous and ethylacetate layers. The solvent in the ethylacetate layer where the product is dissolved was removed on an evaporator, and the residual solid was dried out in a vacuum oven for 24 hours to yield a white 4-(4-acrylaminophenyl)butyric acid (APB) solid (yield 92%). The melting point of the solid was 107° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: O=c1c2cc(Br)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Br)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 47.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2b (200 mg, 0.519 mmol), 6-mercaptopurine monohydrate (97 mg, 0.570 mmol), K2CO3 (79 mg, 0.572 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 123 mg of an off-white solid (47%), mp 212-242° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 13.07 (br s, 1H); 8.48 (s, 1H); 8.44. (s, 1H); 8.24 (d, J=2.3 Hz, 1H); 8.06 (dd, J=2.3, 8.7 Hz, 1H); 7.76 (dd, J=1.9, 7.4 Hz, 1H); 7.70 (d, J=8.7 Hz, 1H); 7.66 (d, J=8.1 Hz, 1H); 7.51 (dd, J=2.1, 7.9 Hz, 1H); 7.46 (dd, J=1.9, 7.9 Hz, 1H); 4.47 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.7, 156.8, 153.6, 151.5, 146.1, 143.6, 138.5, 134.0, 132.1, 131.8, 131.5, 130.5, 130.2, 129.9, 128.9, 128.8, 122.2, 120.3, 32.0. MS (ES): m/z 499.0 (M+). Anal. calcd. for C20H12ClBrN6OS.0.2C2H6O.0.05KCl: C, 47.79; H, 2.59; N, 16.39; S, 6.25. Found: C, 47.56; H, 2.54; N, 16.25; S, 6.58.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:2]1.[CH3:15][C:16]1([CH3:33])[O:20][CH:19]([CH2:21]OS(C2C=CC(Cl)=CC=2)(=O)=O)[CH2:18][O:17]1.CC(C)([O-])C.[Na+].O>O1CCOCC1>[CH3:15][C:16]1([CH3:33])[O:20][C@H:19]([CH2:21][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:2]2)[CH2:18][O:17]1
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1
Reactant: CC1(C)OCC(COS(=O)(=O)c2ccc(Cl)cc2)O1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)c3ccccc3)n2)O1
Temperature: 10 °C
Yield: 49.8 %

Procedure:
N-(1H-Pyrazol-3-yl)-benzamide (2.5 g, 20 mmol) and 4-Chloro-benzenesulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (6.75 g, 22 mmol) were dissolved in anhydrous 1,4-dioxane (30 ml). Sodium tert-butoxide (2.28 g, 23.8 mmol) was added in one portion at room temperature. The yellow suspension was heated to reflux with agitation for 23 hrs. The mixture was cooled to 10° C., water (80 ml) was added. The mixture was extracted with ethyl acetate (30 ml*2), the organic layer was washed with 1N NaOH (20 ml), 10% aqueous NaCl (40 ml*2). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give the crude product as oil. Purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (3 g), yield: 50%. 1H-NMR (400 MHz, d6-DMSO): δ 10.86 (s, 1H), 7.99-8.01 (d, 2H), 7.67 (s, 1H), 7.47-7.58 (m, 3H), 6.63 (s, 1H), 4.4-4.42 (m, 1H), 4.16-4.38 (m, 2H), 4.01-4.05 (m, 1H), 3.75-3.78 (m, 1H), 1.33 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:30][C:31]1[N:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:15]([C:17]1[CH:27]=[C:26]([O:28][CH3:29])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.ClCCl.[C:54]1(=O)[CH2:57]C[CH2:55]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[C:31]([CH2:30][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH:6]2[CH2:57][CH2:54][CH2:55]2)[C:15]([C:17]2[CH:27]=[C:26]([O:28][CH3:29])[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[N:32]=1
Reactant: O=C1CCC1
Reactant: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2

Procedure:
Experimental conditions analogous to Example 1, from 172 mg (0.31 mmol) of (S)-2-{[cinnolin-3-ylmethyl-(7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3 mL 10% trifluoroacetic acid/dichloromethane. The crude deprotected material was submitted to reductive amination reaction in 5 mL dichloromethane using 108 mg (1.55 mmol) of cyclobutanone and 329 mg (1.55 mmol) sodium triacetoxyborohydride. The reaction mixture was purified using flash chromatography elution with 0-10% methanol in dichloromethane, gave 47 mg of pale yellow solid as the free base. LC-MSD, m/z for C29H34N4O4 [M+H]+: 503.7. 1H NMR (400 MHz, CDCl3): δ 1.6-2.5 (m, 16 H), 2.8-2.9 (m, 1 H), 3.5-3.8 (m, 3 H), 3.8 (s, 3 H), 3.9-4.0 (m, 2 H), 5.1-5.3 (m, 2 H), 6.8 (bs, 1 H), 7.2 (bs, 1 H), 7.7-7.9 (m, 4 H), 8.4-8.5 (m, 1 H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12](O)[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.IC.[CH3:18][OH:19].[CH2:20]1COCC1>>[CH3:18][O:19][CH:12]([CH2:13][O:14][CH3:20])[CH2:11][O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: CO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCC(COCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (384 mg) was added to a solution of (±)-3-benzyloxy-1,2-propanediol (0.659 ml) in THF (15 ml). The mixture was stirred for 30 min at RT and iodomethane (0.606 ml) was added. The reaction mixture was stirred on at RT. MeOH was added, then water and the mixture was extracted with DCM. The org. phases were dried (Na2SO4) and evaporated off to afford 841 mg of the desired compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: Fc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(F)ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At −10° C., 90% fuming nitric acid (25 mL) was added to concentrate sulfuric acid (50 mL) slowly to keep the temperature below 0° C. At −20° C. 1-fluoro-4-trifluoromethoxy-benzene (5 g, 27.7 mmol) was added portionwise to keep the temperature of the reaction mixture below 0° C. After addition, the reaction mixture was kept at 0° C. for 30 min, poured into ice-water, extracted with EtOAc. The extracts were concentrated to give a mixture (6.05 g) of 4-fluoro-2-nitro-1-trifluoromethoxy-benzene and 1-fluoro-2-nitro-4-trifluoromethoxy-benzene in a 3:1 ratio. The crude nitration product (6.05 g) was dissolved in ethanol (40 mL) and shacked with 10% Pd/C (310 mg) and concentrate HCl (2.8 mL) under H2 (50 psi) for 3.5 h. Filtration and concentration gave a mixture (8.0 g) of 5-fluoro-2-trifluoromethoxy-phenylamine and its isomer 2-fluoro-5-trifluoromethoxy-phenylamine in 3:1 ratio. Without purification, the phenylamines (7 g, 35.8 mmol) were suspended in dichloromethane (100 mL), treated with trifluoroacetic anhydride (71 mmol) and triethylamine (20 mL) for 16 h. The reaction mixture was washed with saturated NaHCO3 and brine. The organic phase was further purified by silica gel chromatography (hexane/EtOAc 9:1) to give a mixture (5.29 g) of 2,2,2-trifluoro-N-(5-fluoro-2-trifluoromethoxy-phenyl)-acetamide and its isomer in 1:4 ratio, which was nitrated in a same procedure as the first step. The nitrate (3 g) was heated under reflux with morpholine (10 mL) in 1,2-dichloroethane (30 mL) for 3 h. Evaporation to remove excess morpholine. The residue was diluted with dichloromethane, washed with HCl (0.5N, 100 mL). The organic phase was purified by FC (hexane/EtOAc 7:3 to 1:1) to give the title compound 5-morpholin-4-yl-4-nitro-2-trifluoromethoxy-phenylamine (2.48 g). LC-MS: m/e=306.1 (M−H), 308.2 (M+H). 1H-NMR (500 MHz, CDCl3): 8.04 (s, 1H), 6.35 (s, 1H), 4.54 (br. s, 1H), 3.90 (t, 4H), 3.07 (t, 4H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:9][O:10][C:11]1[C:25]([CH2:26][Br:1])=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1C(=O)c1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(CBr)cccc1C(=O)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
A mixture of 1.78 g of N-bromo-succinimide and 10 mg of benzoyl peroxide was added to a suspension of 2.6 g of 2-methoxy-3-methyl-4'-chlorobenzophenone in 15 ml of carbon tetrachloride and the solution was refluxed for 4 hours. The insolubles were removed by filtration and the filtrate was evaporated to dryness to obtain 3.32 g of 2-methoxy-3-bromomethyl-4'-chlorobenzophenone in the form of a clear yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:32])[CH2:13][S:14][CH:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[C:17](=[O:22])[N:16]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[S:9][CH:10]=1)C.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:16]2[C:17](=[O:22])[C:18]([CH3:21])=[C:19]([CH3:20])[CH:15]2[S:14][CH2:13][C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:33])=[O:3])[N:7]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2nc(CC(=O)O)cs2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
The product from Example 7 (100 mg, 0.2 mmol) was dissolved in 4 mL THF and cooled to 0° C. LiOH (56 mg, 0.8 mmol) in 4 mL water was added dropwise. The mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to 0° C. and diluted with 10 mL EtOAc. 2N aq HCl was added until the mixture reached pH1. The aqueous phase was washed with EtOAc. The combined organics were washed with water, dried (Na2SO4), filtered, and evaporated. Recrystallization fro ether/hexane provided the title compound as a tan powder (60 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=9 Hz, 2H), 6.81 (m, 3H), 5.02 (d, J=15 Hz, 1H), 4.55 (s, 1H), 4.15 (d, J=15 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 2H), 3.11 (d, J=15 Hz, 1H), 2.96 (d, J=15 Hz, 1H), 1.89 (s, 3H), 1.76 (s, 3H). MS: m/z (MH+) 462.
Reaction SMILES: C(OP(OCC)([CH:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O)C.C=O.[C:21](=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[CH3:15][CH:13]([CH3:14])[CH2:12][C:6](=[CH2:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(CC(C)C)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=C(CC(C)C)C(=O)OCC
Yield: 63.3 %

Procedure:
A mixture of 19 g (67.9 mmol) of ethyl 2-(diethoxyphosphinyl)-4-methylpentanoate, 27 ml (360.3 mmol) of formaldehyde and 28 g (202.6 mmol) of potassium carbonate is maintained at reflux for 3 hours. A mixture of water and diethyl ether is added. The aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is distilled under reduced pressure. 6.7 g of product are recovered in the form of an oil (yield=63.3%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccn1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccn3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A mixture of 2-phenyl-1-(pyridin-2-yl)ethanone (Intermediate 27) (200 mg, 1.01 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (214.1 mg, 1.01 mmol), urea (182.5 mg, 3.04 mmol), and concentrated hydrochloric acid solution (0.3 mL) in ethanol (1 mL) was refluxed for 60 h. After being cooled down to room temperature, the mixture was evaporated, and purified by preparative HPLC to give Compound 59 (132.5 mg, yield 30.2%). 1H NMR (DMSO-d6 400 MHz): δ10.26 (brs, 1H), 8.59 (d, J=4.4 Hz, 1H), 8.37 (s, 1H), 7.62-7.54 (m, 2H), 7.42 (s, 1H), 7.30-7.27 (m, 1H), 7.14 (d, J=6.4 Hz, 4H), 6.93-6.90 (m, 3H), 5.25 (s, 1H), 4.03-3.99 (m, 2H), 1.33-1.29 (m, 3H); MS (ESI): m/z 433.0 [M+H]+.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)c([N+](=O)[O-])c1

Procedure:
5 g of 2-hydroxy-5-methyl-3-nitropyridine are dissolved in 32 cm3 of thionyl chloride to which 2 cm3 of N,N-dimethylformamide have been added. The mixture is then brought to reflux for 2 hours. After removing the solvent under partial vacuum, the product is distributed between distilled water (30 cm3) and chloroform (3×100 cm3). The chloroform fractions are combined, dried over MgSO4, filtered and then concentrated under vacuum. The residue is recrystallized from ethanol/water. Yd.: 60-65%
Reaction SMILES: [ClH:1].O1[C:6]2([CH2:11][CH2:10][CH:9]([C:12]([O:14]C(C)(C)C)=O)CC2)[CH2:5][NH:4][CH2:3]1.[CH3:19]O>>[ClH:1].[O:14]1[C:11]2([CH2:19][CH2:3][NH:4][CH2:5][CH2:6]2)[CH2:10][CH2:9][CH2:12]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)C1CCC2(CC1)CNCO2
Agent: Cl
Product: C1COC2(C1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Methanolic hydrogen chloride (3M, 20 ml) was added over 10 minutes to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iv) above, 3.18 g, 13.2 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give the title compound (2.29 g, 98%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22]>CO.C(O)(=O)C>[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C)cn1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1C)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl-5-methylpyridine (1.00 g, 7.40 mmol) and 1-methyl-2-hydrazinobenzimidazole (1.20 g, 7.40 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV234 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water: Yield: 1.54 g (73% of theory).