Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH2:2][CH3:3].[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].N1CCCCC1.O>C(O)C>[C:13]([C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:1][CH2:2][CH3:3])[CH:5]=1)#[N:14]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: CCOc1cc(C=C(C#N)C(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of 20 grams of 3-ethoxyl-4-hydroxybenzaldhyde and 13 grams of methyl cyanoacetate in 100 ml of ethanol was refluxed with 1 ml of piperidine for 4 hours. The crude mixture was allowed to cool down to room temperature and, with stirring, water was added until the solid began to form. This mixture was then refrigerated for 4 hours and solids was collected by suction filtration, washed with a cold mixture of ethanol and water (1:2) and suction dried to provide 25 grams of 1-cyano-2-(3-ethoxy-4-hydroxyphenyl)-1-methoxycarbonyl ethene.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20]Cl)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][S-:23].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][S:23][CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCl
Reactant: C[S-]
Agent: [Na+]
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCSC
Yield: 93.5 %

Procedure:
Using the general method of Example 21 Part D, 2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline-4-amine (1.44 g, 4.76 mmol) was reacted with sodium thiomethoxide (0.42 g of 95%, 5.71 mmol) to provide 1.4 g of 2-butyl-1-[2-(methylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:18]CN=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[C:24]([NH:27]N)(=O)[CH3:25].C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:24]([CH3:25])=[N:27][N:18]=[C:7]3[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reactant: CC(=O)NN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reaction time: 72 h

Procedure:
A mixture of 3.3g (0.01M) of 7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one, 2g of acetylhydrazine, 5 ml of triethylamine and 50 ml of n-butanol was heated to reflux for 3 hrs. Half of the solvent was then removed by distillation and replaced by fresh n-butanol. Refluxing was continued for 3 days. The residue obtained after evaporation was chromotographed over 100 g of silical gel(Merck 70-230 mesh) using 10% (v/v) ethanol in methylene chloride for elution. Crystallization of the pure fraction from methylene chloride/ether yielded the above maned product, m.p. 298°-300°.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>ClCCl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]([NH2:16])=[O:15])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC(=O)c1cccn1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cccn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (3.10 ml, 22.4 mmol) is added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (1.25 g, 10.0 mmol) in dichloromethane (13 ml). Then 4-bromo-benzoyl chloride (2.19 g, 10.0 mmol) is added slowly. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with water and 1 N HCl. The organic phase is evaporated to give crude 1-(4-bromo-benzoylamino)-1H-pyrrole-2-carboxylic acid amide as light orange solid, which is used as such in the next reaction; HPLC/MS 1.56 min (C), [M+H] 308/310.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:10]([CH3:26])([CH3:25])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:10]([CH3:25])([CH3:26])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc([N+](=O)[O-])c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a mixture of 4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (30 g, 81 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (12 g, 41%) as a white solid: LC/MS m/e calcd for C20H22N2O4 (M+H)+: 355.41, observed: 355.1.
Reaction SMILES: CC(S([NH:7][C:8]([CH3:20])([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)[CH2:9][CH:10]1[CH2:13][O:12][CH2:11]1)=O)(C)C.Cl.O1CCOCC1>CO.C(OCC)(=O)C>[CH3:19][C:16]1[O:15][C:14]([C:8]([NH2:7])([CH3:20])[CH2:9][CH:10]2[CH2:11][O:12][CH2:13]2)=[N:18][N:17]=1
Reactant: Cc1nnc(C(C)(CC2COC2)NS(=O)C(C)(C)C)o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nnc(C(C)(N)CC2COC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
To a solution of 2-methyl-N-[1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(oxetan-3-yl)ethyl]propane-2-sulfinamide (example 190c, 250 mg, 829 μmol) in methanol (8 ml) was added a 4M solution of hydrochloric acid in dioxane (415 μl, 1.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted twice with ethylacetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the title compound (168 mg) as a crude oil which was used without any purification. MS (ESI, m/z): 198.3 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH2:25][CH3:26])=[C:14]([CH2:23]O)[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]2[CH:9]=[N:8]1)[CH3:6]>>[Cl:3][CH2:23][C:14]1[C:13]([CH2:25][CH3:26])=[N:12][C:11]2[N:7]([CH2:5][CH3:6])[N:8]=[CH:9][C:10]=2[C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To the solution of thionyl chloride (1.46 mL, 20.0 mmol) was added [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (0.609 g, 2.0 mmol) slowly. The mixture was stirred at room temperature for about 30 mins before it was concentrated on rotavap under vacuum. DCM (5 ml) was added to the residue and concentrated on rotavap twice to afford 0.386 g (60%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].C([O-])(=O)C.[Na+].[Cl-].[C:21]1([CH:27]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:28][NH3+:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:29][CH2:28][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[C:3]1=[O:14]
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Reactant: [NH3+]CC(c1ccccc1)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c(CNCC(c2ccccc2)C2CCOCC2)cc2ccccc21
Reaction time: 20 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (35 mg, 0.187 mmol), sodium acetate (19.94 mg, 0.243 mmol), and 2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethanaminium chloride (45.2 mg, 0.187 mmol) were combined in 1,2 dichloroethane (2 ml). Acetic acid (0.021 ml, 0.374 mmol) and sodium triacetoxyborohydride (119 mg, 0.561 mmol) were added and the reaction stirred for 20 hours. The mixture was partitioned between CH2Cl2 and satd. bicarb and the aqueous portion was extracted 3×CH2Cl2. The organic portion was dried (Na2SO4) and concentrated in vacuo. The resulting material was purified by reversed-phase chromatography (10-60% ACN in water (with 2 ml/l NH4OH) over 20 min at 20 ml/min, 20×100 mm Phenomenex Gemini C18 column). Desired fractions were concentrated in vacuo. 50.5 mg, 73%.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[CH:7]=[CH:6][C:5]=12.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=O)[CH:19]=[CH:20][CH:21]=1>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=3)=[N:12][N:13]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NNC(=O)c1ccc2nccn2c1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CCc2nnc(-c3ccc4nccn4c3)o2)c1
Yield: 58 %

Procedure:
In the same manner as in Example 14 and using imidazo[1,2-a]pyridine-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-[3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 58%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N+:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 66 h
Yield: 88.6 %

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 3a) (18.54 g, 69.0 mmol) and 4-nitrobenzohydrazide (12.5 g, 69.0 mmol) in anhydrous THF (400 mL) was added 1-Hydroxybenzotriazole monohydrate (10.57 g, 69.0 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (26.46 g, 138.0 mmol) at −45° C. followed by triethylamine (19.2 mL, 138.0 mmol). The reaction mixture warmed to room temperature and stirred for 66 h, then quenched with 5% aq. citric acid (350 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×300 mL), sat. aq. NaHCO3 (3×300 mL), H2O (2×300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a yellow solid (26.4 g, 89%): 1H NMR (400 MHz, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.59 (d, J=7.2 Hz, 1H), 4.29 (pentet, J=5.3 Hz, 1H), 4.17 (dd, J=5.1, 7.2 Hz, 1H), 2.36 (s, 3H), 1.40 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([S:28]([NH:14][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:9]([C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Product: COc1ncccc1-c1cc(C(=O)NS(=O)(=O)C2CC2)ccc1Oc1ccccc1
Yield: 17 %

Procedure:
Prepared according to Example 5 with 3-(2-methoxypyridin-3-yl)-4-phenoxybenzamide (Preparation 19, 0.030 g, 0.09 mmol) and cyclopropylsulfonyl chloride (0.030 g, 0.21 mmol). The product was purified by preparative HPLC to afford the title compound as a white solid (6.5 mg).
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1CCCCC1>[NH:27]1[CH2:28][CH2:29][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=4[CH2:3][C:2]([NH2:1])=[O:41])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-1-carboxylate (I141) in DCM (20 mL) was added TFA (4.0 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue taken up in EtOAc (10 mL) and 2 M NaOH (10 mL). The organic layer was extracted with EtOAc (2×10 mL), and the combined layers washed with water (10 mL), brine (10 mL) and dried over MgSO4. The solvent was removed in vacuo to give a yellow solid. The solid was suspended in cyclohexane and filtered to give a brown solid (42 mg). The product was purified further by RP-HPLC (Waters, 0-80% CH3CN in H2O over 20 minutes at a flow rate of 10 mL/min). Fractions containing product were basified (pH 10) with 2 M NaOH and extracted with EtOAc. The combined organic layers were washed with brine (10 mL), dried (MgSO4) and the solvent removed in vacuo to give the title compound (35) (17 mg, 27%) as a brown oil; 1H-NMR (400 MHz, d4-MeOD) δ 8.56 (d, J=0.6 Hz, 1H), 7.73-7.68 (m, 2H), 7.33-7.16 (m, 6H), 3.67 (s, 2H), 3.60-3.46 (m, 2H), 3.42-3.33 (m, 2H), 3.14 (m, 5H), 2.45 (dtd, J=10.1, 7.1, 3.4 Hz, 1H), 2.18-2.05 (m, 1H); LCMS Method C: rt 4.84 min; m/z 470.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][C:12](OC(C)(C)C)=O)[CH:5]=1.[CH2:21](Br)[CH:22]=C.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][CH2:12][CH:21]=[CH2:22])[CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(=O)c1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonylacetyl-benzoic acid methyl ester (11.1 g) and allyl bromide (3.0 mL) in DMF (40 mL) was added portionwise at 0° C. NaH (55% dispersion in mineral oil, 1.44 g). Stirring was continued at 0° C. for 20 min and at 20° C. for 30 min. The mixture was partitioned between AcOEt and brine, the pH being set to 7 by the addition of 3N HCl. The organic layer was dried and evaporated. The residual oil was stirred in a mixture of CH2Cl2 (30 mL) and TFA (30 mL) for 40 min at 20° C. The solvents were evaporated. The solution of the residue in AcOEt was extracted with ice-cold sat. Na2CO3 solution and the aqueous extracts were immediately acidified with 3N HCl and extracted with AcOEt. The solvent of this extract was evaporated and the residue heated in a mixture of toluene (40 mL) and 3N HCl (2 mL) to 100° C. for 1 h. The cooled mixture was diluted with AcOEt, washed with sat. NaHCO3 and brine, dried and evaporated to give 3-pent-4-enoyl-benzoic acid methyl ester (5.11 g) as a pale-yellow oil, MS (ISP) 236.2 [(M+NH4)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>CC(O)CCC.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCC(C)O
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To the solution of (E)-1-chloro-4-(4-(2-nitrovinyl)phenoxy)-2-(trifluoromethyl)benzene (640 mg, 1.862 mmol) in 2-pentanol (5 mL) and chloroform (15.00 mL) was added silica-gel (2 g), and then NaBH4 (282 mg, 7.45 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was purified via a flash column affording the title compound (330 mg, 49.2% yield). LCMS: rt=4.62 min, [M+H+]=NA
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[CH:22]([NH:24][C:25](=[O:27])[CH3:26])=[CH2:23].C(N(CC)CC)C.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]([C:22]([NH:24][C:25](=[O:27])[CH3:26])=[CH2:23])[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: C=CNC(C)=O
Reactant: O=S(=O)(Oc1cccc(C(F)(F)C(F)(F)F)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(NC(C)=O)c1cccc(C(F)(F)C(F)(F)F)c1
Temperature: 130 °C

Procedure:
To a solution of the crude product of step 1 (0.75 g, 2.2 mmol) in DMF (10 ml) was added N-vinylacetamide (0.37 g, 4.36 mmol), triethylamine (243 mg, 0.33 ml, 2.40 mmol), palladium acetate (20 mg, 4 mol %) and bis(diphenylphosphino)propane (40 mg, 0.1 mmol). The reaction mixture was heated for 30 min at 130° C. using microwaves. The red solution was diluted and washed with hydrochloric acid (1M, 2×15 ml) and sodium hydrogen carbonate (saturated, 20 ml). The organic phase was dried over sodium sulphate and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane (2:1) gave the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][S:22][CH3:23])[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][S:22][CH3:23])[CH2:18][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([CH3:10])([CH3:12])[CH3:11]
Reactant: Nc1cccc(Cl)c1
Reactant: CSCC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CSCC[C@@H](CNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product from Step G (23.9 g, 97.4 mmol), and acetic acid (27.8 mL, 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol). The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The solution was diluted with CHCl3, and the organic phase was washed with water, 10% citric acid and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with 20% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:3]1=[O:27].C([N-]C(C)C)(C)C.[Li+].[I:36]I.[Cl-].[NH4+]>O1CCCC1>[I:36][C:9]1[N:10]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:5]2[C:6]=1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:27])[N:4]2[CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)cc21
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Temperature: -78 °C

Procedure:
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione ((J. Med. Chem., 1995, 38, 2557; 500 mg) was dissolved in tetrahydrofuran (15 ml) and cooled to −78° C. A solution of lithium diisopropylamide (2 eq) in tetrahydrofuran (5 ml) was added dropwise with stirring at −78° C. Iodine (350 mg) was added and the reaction mixture was allowed to stir at −78° C. for 1 hour and was then allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic phases were washed with sodium thiosulphate solution, and with brine, before being dried and evaporated. The resultant foam was chromatographed using isohexane:diethyl ether (1:3) to give a foam which was recrystallised from diethyl ether/isohexane to give the subtitle compound as a pale yellow solid (350 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1)#[N:2].CN(C=O)C.[OH:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:19][N:20]2[C:21](=[O:30])[C:22]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]3[C:24]2=[O:25])=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1)#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOc1cc(C#N)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C#N)ccc1CON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Into a reaction vessel was charged 4-cyano-2-ethoxy-α-bromotoluene (16) (20.2 g, 0.084 mol) and N,N′-dimethylformamide (200 ml), and N-hydroxyphthalimide (14.4 g, 0.088 mol) and anhydrous potassium carbonate (12.2 g, 0.088 mol) were added to this, and the mixture was stirred for 2 hours at approximately 80° C. Water was added to the reaction liquid and the precipitated solid was filtrated. This was dried, to obtain N-(4-cyano-2-ethoxybenzyloxy)phthalimide (17) (27.0 g, yield from (16) is 99%).
Reaction SMILES: O=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4](OCC)=[O:5].[NH2:15][NH2:16]>CCO>[O:5]=[C:4]1[NH:16][NH:15][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3]1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: NN
Solvent: CCO
Product: CCOC(=O)Cc1cc(=O)[nH][nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a solution of diethyl 3-oxopentanedioate (26.0 g, 129 mmol) in EtOH (250 mL) was added hydrazine (4.38 g, 129 mmol) at room temperature, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diethyl ether-hexane to give the title compound as a white powder (9.79 g, 45%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([N+:14]([O-])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5]OC[CH2:2]1.N1CCC1>>[N:1]1([C:7]2[N:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Agent: C1CNC1
Product: Nc1cnc(N2CCC2)cc1N

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 151.1 and 151.2, except azetidine was used in place of morpholine.