Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:19][CH:18]=3)[N:14]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]2=[N:12][CH:13]=1)=O)#[N:2].[N-:37]=[N+:38]=[N-:39].[Na+].N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[C:27]([Si:24]([CH3:25])([CH3:26])[O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]3=[N:12][CH:13]=[C:8]([C:6]4[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:39]=[N:38][N:37]=4)[CH:9]=[C:10]3[N:16]=2)=[CH:22][CH:21]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C(=O)NCCC#N)cnc3n2C2CCCCC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnnn4CCC#N)cnc3n2C2CCCCC2)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
A solution of intermediate 61 (250 mg, 0.5 mmol), sodium azide (33 mg, 0.5 mmol), and 2,6-lutidine (116 μL, 1.0 mmol) in dichloromethane (3 mL) was cooled to 0° C. and trifluoromethanesulfonic anhydride (84 μL, 0.5 mmol) from a freshly opened ampule was added under a nitrogen atmosphere. The reaction mixture was allowed to warm up slowly to rt over 2 h and stirring continued for 20 h at which point dichloromethane was added (25 mL). The resulting organic phase was washed with saturated NaHCO3 (1×20 mL), dried (Na2SO4), and concentrated on a rotary evaporator. The foamy residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford intermediate 62 as a white solid (48 mg, 18%). ESI-MS m/e 529.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14]Cl)[CH:13]=1>>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:13]=1
Reactant: ClCc1cncc(Br)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], 2-methyl-imidazol has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a light brown solid. MS: 251.9, 254.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12](C(O)=O)[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[ClH:19].O1CCOCC1>CO>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1N1CCCN(C(=O)O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccnc1N1CCCNCC1
Reaction time: 15 h

Procedure:
To 4-(3-methoxypyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tent-butyl ester (335 mg, 1.1 mmol) was added MeOH (3 mL) followed by 4M HCl in dioxane (5 mL, 20 mmol). This was stirred for 15 hours, then concentrated to give the title compound. MS (ES) m/z 208 (M+H+).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([OH:20])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([O:20][C:3](=[O:4])[NH:2][CH3:1])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CNC(=O)OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 81.2 %

Procedure:
5.7 g (0.1 mol) of methyl isocyanate and a few drops of dibutyl-tin dilaurate were added to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(imidazol-1-yl)-ethane in 250 ml of benzene, while stirring. The mixture was stirred overnight at 60°-65° C. It was then allowed to cool and the crystalline precipitate was filtered off and rinsed with ether. 25.5 g (81% of theory) of 1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-methylcarbamoyloxy-ethane of melting point 106°-108° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([CH3:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([Br:16])[C:13]([CH3:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)Cc1ccc(OC(C)C)c(Br)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(Br)c1ccc(OC(C)C)c(Br)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 100 mg (0.369 mmol) of 1-(3-bromo-4-isopropoxyphenyl)acetone (from Example 228, Step C) in toluene (0.26 mL) was added bromine (0.019 mL, 0.369 mmol) dropwise via syringe. After stirring 30 min. At RT, a solution of sodium sulfite (676 mg) in water (1.5 mL)) was added and the mixture was extracted with 3×15 mL of ethyl ether. The combined organic layers were washed 20 mL of saturated sodium bicarbonate followed by 20 mL of brine. Drying over sodium sulfate and evaporation gave 119 mg of product as a red oil. Mass spectrum (NH3/CI): m/z=349 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].O.[SH-:13].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([SH:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: [SH-]
Reactant: COC(=O)c1nccnc1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nccnc1S
Temperature: 25 °C
Reaction time: 9 h
Yield: 89.4 %

Procedure:
After 3-chloro-pyrazine-2-carboxylic acid methyl ester (0.4 g, 2.3 mmol) was dissolved in MeOH (46 mL), sodium hydrosulfide monohydrate (0.65 g, 6.9 mmol) was added thereto, and the mixture was stirred at room temperature for 9 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl aqueous solution was used to adjust the pH of the reactant to 3. The reactant was extracted with EtOAc, and the organic layer was separated to obtain the title compound (0.35 g, 89%).
Reaction SMILES: N[C@@H:2]([CH:11](C)C)[C@@H:3]([C:5]1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].CCCCCC>CCOC(C)=O>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:5][CH2:3][CH2:2][CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCC1
Yield: 93 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenyl-ethanol. Column chromatography (Silica gel, eluent is n-Hexane:EtOAc=5:1) is used to purify the coarse product and a white solid (1.24 g) is obtained. The yield is 93% and the other analysis includes:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH:18]([NH2:22])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].Cl>C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH:18]([NH:22][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Yield: 52.1 %

Procedure:
Dissolve 9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine (Preparation 47) (580 mg, 1.53 mmol) and triethylamine (201 mg, 277 μL, 1.99 mmol) in CH2Cl2 (20 ML). Slowly add isobutyryl chloride (212 mg, 208 μL, 1.99 mmol) and stir at room temperature for 18 h. Dilute the reaction with dilute HCl (10 mL), then load the reaction onto a Varian ChemElut CE1020 solid-phase extraction cartridge (Varian part number 12198008). Elute, collect, and concentrate 125 mL CH2Cl2 to give the crude product (794 mg) as a brown oil. Purify the crude product on silica gel (40 g), eluting with 35-65% EtOAc/hexanes to afford 358 mg (52%) of the title compound as a yellow foam. MS (ES): m/z 450 (M+1), 448 (M−1); HPLC (Method B): Rt=8.21 min (100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[F:16])[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:4].[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[F:16])[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)CBr)c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c1
Yield: 84.8 %

Procedure:
3'-(2-Bromoacetyl)-4'-fluoromethanesulfonanilide (30 g) was dissolved in 200 ml of N,N-dimethylformamide, a solution of 38 g of dibenzylamine in N,N-dimethylformamide was added with ice-cooling and stirring and the mixture was made to react at room temperature for 1 hour. The reaction mixture was added to water followed by extracting with ethyl acetate. The extract was washed with water, dried, the solvent was evaporated therefrom and the residue was crystallized from diisopropyl ether to give 35 g of 3'-(2-dibenzylaminoacetyl)-4'-fluoromethanesulfonanilide. The crystals were made into hydrochloride to give 35 g of crystals, m.p. 185°-188° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5]1)#[N:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CCC1CC(C(=O)O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC1CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyanomethylcyclobutane carboxylic acid (4.0 g, 28.8 mmol) in dichloromethane (50 ml) was added two drops of dimethylformamide followed by oxalyl chloride (12 ml). The mixture was stirred overnight at room temperature followed by removal of the solvent and excess reagent in vacuo. The resulting oil was dissolved in dry dichloromethane and the solvent evaporated to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.N1C=CC=CC=1.Cl.[NH2:19][OH:20]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:19][OH:20])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CCc2cc(F)ccc21
Yield: 96.9 %

Procedure:
4.5 g (30 mmol) of 5-fluoro-1-indanone and 20 ml of pyridine and 20 ml of ethanol were heated to 80° C. with 2.3 g (33 mmol) of hydroxylamine hydrochloride for 6 h. The solvents were distilled off, the residue was stirred with water and the precipitate was filtered off with suction and dried under reduced pressure. This procedure gave 4.8 g of 5-fluoro-1-indanoneoxime; m.p. 150-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20](F)[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[F:30][C:31]([F:36])([F:35])[C@@H:32]([OH:34])[CH3:33]>CCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:34][C@@H:32]([CH3:33])[C:31]([F:36])([F:35])[F:30])[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](Oc1cc(C[C@@H]2CSC[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 24j, starting from [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.409 g, 1 mmol), KOH (0.06 g, 1.05 mmol) and (S)-1,1,1-trifluoro-propan-2-ol (0.583 g, 5 mmol) and was obtained as a yellow oil, which was used as such in the next step: TLC (hexane-EtOAc 1:1) Rf=0.37; HPLC RtA=2.36 min; ESIMS [M+H-isobutylene]+=443.
Reaction SMILES: [C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:34][CH3:35])[C:32]=1[CH3:33])[C:27](Cl)=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([C@H:5]([N:9]([C:27](=[O:28])[C:26]1[CH:30]=[C:31]([O:34][CH3:35])[C:32]([CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1)[NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C
Reactant: CCC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC[C@@H](N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C
Temperature: 25 °C

Procedure:
(R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-butyl)-hydrazide (100 mg, 0.34 mmol) and 3,5-dimethoxy-4-methyl-benzoyl chloride (90 mg, 0.41 mmol) were dissolved in 1 mL methylene chloride. 1.5 eq. of ca. 25% K2CO3 was added, and the reaction mixture was stirred at room temperature and monitored by TLC. Upon completion, the phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 phase was dried over MgSO4 or Na2SO4, and solvent was removed in vacuo to provide an oily solid. This was triturated with 1:1 hexane:ether and allowed to dry in air to yield (R)-3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. Rf=0.29 (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.1 (t, 1H), 7.0 (s, NH 1H), 6.9 (d, 1H), 6.7 (s, 2H), 6.3 (d, 1H), 4.78 (m, 1H), 3.95 (s, 3H), 3.85 (2 s, 6H), 2.2 (s, 3H), 2.05 (m, 1H), 1.95 (s, 3H), 1.8 (m, 1H), 1.6 (m, 2H), 1.2+1.1+1.05 (3 s, 9H), 1.05 (m, 3H); HRMS (ESI) m/z calcd for C27H39N2O5 [M+H]+ 471.2859, found 471.2850, calcd for C27H38NaN2O5 [M+Na]+ 493.2670, found 493.2678.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:19][N+:20]([CH3:29])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:21]([N:20]([CH3:19])[CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: Cc1ccccc1C=[N+](C)C
Agent: [Cl-]
Product: Cc1ccccc1C(c1c[nH]c2ccc(OCc3ccccc3)cc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole and dimethyl-(2-methyl-benzylidene)-ammonium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]3[N:16]([CH3:31])[C:17](=[O:30])[N:18]([C:20]4[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=4[CH3:29])[CH2:19][C:13]3=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=O)C>[Pd].CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([CH3:29])=[C:20]([N:18]2[CH2:19][C:13]3[C:14](=[N:15][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH3:32])[CH:4]=4)=[N:11][CH:12]=3)[N:16]([CH3:31])[C:17]2=[O:30])[CH:25]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(N)cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a solution of 7-(3-dimethylamino-phenylamino)-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (80 mg, 0.18 mmol) in the mixed solvent of DMF (3 ml) and methanol (3 mL) is added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give 3-(5-amino-2-methyl-phenyl)-7-(3-dimethylamino-phenylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (60 mg, 81%) as a dark yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S(O[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCOCCn1ccnc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
In a nitrogen atmosphere, a mixture of 68.0 g of imidazole, 318 g of 2-[2-(2-methoxyethoxy)ethoxy]ethyl p-toluenesulfonate, 276 g of potassium carbonate, and 1,000 g of N,N-dimethylformamide was heated and stirred at 100° C. for 16 hours. To the reaction solution was added ethyl acetate. The precipitate was filtered off, after which the solvent was distilled off in vacuo. The residue was purified by distillation in vacuo, obtaining 163 g of 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-1H-imidazole (boiling point 121° C./16 Pa, yield 76%).
Reaction SMILES: [O:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[CH3:10][C:11]1[NH:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:3]1([CH2:2][N:15]2[C:11]([CH3:10])=[CH:12][CH:13]=[C:14]2[C:16]#[N:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(C#N)[nH]1
Reactant: C1CCCC2(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)n1CC1(O)CCCCCC1

Procedure:
1-Oxaspiro[2,6]nonane (2.5 g), 5-methyl-1H-pyrrole-2-carbonitrile (2.1 g) and Cs2CO3 (6.45 g) in N,N-dimethylformamide (15 mL) was heated at 120° C. in a Biotage Initiator microwave reactor for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by reverse phase chromatography, and was eluted with 30%-70% acetonitrile in 0.1% TFA water solution to provide the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2ccc(C(F)(F)F)cc2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.7 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 11.5 g of 4-trifluoromethylbenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then 30 minutes at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 155°-156° C.). 1H NMR (CDCl3) δ2.83 (dd, 1H), 2.99 (dd, 1H), 3.58 (dd, 2H), 5.76 (dd, 1H), 7.50-7.76 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].[C:12]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>C(OCCO)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:2]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:22][CH:21]([OH:23])[CH2:20][O:19][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])(=[O:3])[CH3:1]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: Cc1ccccc1OCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1c(O)cccc1OCC(O)COc1ccccc1C
Yield: 60.8 %

Procedure:
A solution of 2,6-dihydroxyacetophenone (15.2 g) and o-cresylglycidyl ether (16.4 g) in 2-ethoxyethanol (75 ml) containing benzyltrimethylammonium hydroxide solution (10 drops; 40%) was heated under reflux for 48 hours. Following removal of the 2-ethoxyethanol under reduced pressure, the resulting solid was washed with ether to give 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-o-cresyloxypropane (19.2 g) as a cream solid, m.p. 101°-102.5° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:16]=[C:15]1[CH2:27][C:28](OCC)=[O:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28](=[O:29])[CH2:27][C:15]2[N:14]([CH3:13])[C:19](=[O:20])[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(CC(=O)Nc2ccc(F)cc2)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.135 ml of 4-fluoroaniline and 0.670 ml of a 2M solution of trimethylaluminium are added, dropwise, to a solution of 190 mg of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 10 ml of toluene. After stirring for 30 minutes at ambient temperature, 10 ml of toluene are added. After stirring for 4 hours at ambient temperature, the reaction mixture is poured into water and a 1M solution of potassium phosphate is added. The precipitate is filtered through sintered glass and then rinsed with ethyl acetate. The filtrate is then washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is extracted and then dried over magnesium sulphate, filtered through sintered glass, and concentrated under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05, V/V), 20 mg of N-(4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:7]=1.C(O)(=O)C>[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)ccc2C(F)(F)F)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2C(F)(F)F)CC1
Yield: 48.8 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.614 g, 1.70 mmol), platinum oxide (0.200 g, 0.881 mmol), acetic acid (1 mL), and ethyl acetate (15 mL) was hydrogenated using a balloon of H2 for 16 h and filtered. After concentration, the residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate as colorless thick oil (0.302 g, 48%): 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J=1.3 Hz, 1H), 4.26 (br, 2H), 3.04 (m, 1H), 2.80 (m, 2H), 1.80-1.55 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 308 [M+H]+.