Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])C.[Na+].[CH3:5][C:6]1[S:10][C:9]([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C(O)C>[CH3:5][C:6]1[S:10][C:9]([C:11]([CH:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18])=[CH:8][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CC(=O)c1ccc(C)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(C(=O)OCC)C(=O)c1ccc(C)s1
Reaction time: 8 h

Procedure:
1.54 g of sodium ethanolate (22.6 mmol), 4.00 g ethyl 3-(5-methylthiophen-2-yl)-3-oxopropanoate (2) and 6.67 g of ethyl bromoacetate are suspended under argon in absolute ethanol at 0° C. The mixture is stirred overnight. Water is added, ethanol is evaporated and the aqueous solution is extracted with diethyl ether. The organic phase is washed with water containing few drops of concentrated HCl, dried and evaporated to provide diethyl 2-(5-methylthiophene-2-carbonyl)succinate (3) which is used without further purification. A mixture of compound 3 and 11.64 g of ammonium acetate in glacial acetic acid is stirred at 120° C. under argon for 4 hours. After cooling to room temperature, the mixture is poured into water. The precipitate formed is isolated by filtration, washed with water and diethyl ether to provide compound 4. 1H NMR (300 MHz, CDCl3) δ 9.57 1H s, 7.61 1H d, 6.81 1H m, 4.24 2H q, 3.53 2H s, 2.54 3H large s, 1.31 3H t.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([O:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: COc1cccc(O)c1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(Oc2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 155 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 3-Methoxyphenol 8e (0.033 g, 0.282 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol). Nitrogen was bubbled through the resultant reaction mixture and heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed, and purified to obtain the desired product which was to obtain 107 as a white solid (15.0 mg, 30%)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:3]=1.[NH2:15][NH2:16]>O1CCOCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[NH:3]/[C:2](=[N:15]\[NH2:16])/[CH:7]=[N:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: Fc1ccc(-c2cncc(Cl)n2)cc1
Solvent: O
Solvent: C1COCCO1
Product: N/N=c1/cncc(-c2ccc(F)cc2)[nH]1
Yield: 88.6 %

Procedure:
A mixture of 2-chloro-6-(4-fluoro-phenyl)-pyrazine (1.0 g, 4.7 mmol) and anhydrous hydrazine (1.5 mL, 47 mmol) in dioxane (20 mL) was heated to reflux for two hours, then cooled and diluted with cold water. The resulting precipitate was collected by filtration, washed with cold water, and dried to give 0.85 g of [6-(4-fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:37][CH2:36]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: COc1ccc(C)cc1N1CCNCC1
Product: COc1ccc(C)cc1N1CCN(C(=O)Nc2cc3ccccc3nc2OC)CC1
Yield: 76 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reactant: CCOC(=O)CCCCBr
Product: CCCc1nc(SCCCCC(=O)OCC)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Stage 7 of Example 1 starting with the product obtained in Stage 6 of Example 1 and ethyl 5-bromo-pentanoate instead of ethyl 4-bromocyclohexaneacetate. In this way the expected product is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH3:23])[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])(=[O:13])=[O:12].Br[CH2:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.Cl>CN(C)C=O.O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:18]1=[O:22])[CH3:23])(=[O:13])=[O:12]
Reactant: CN(CCN1CCNC1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: N#Cc1ccc(CCBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCN1CCN(CCc2ccc(C#N)cc2)C1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
34 mg (0.84 mmol) of NaH (60%) were added to a solution of 290 mg (0.82 mmol) of 2,3-dichloro-N-methyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 177 mg (0.84 mmol) of 4-(2-bromoethyl)benzonitrile were then added. The reaction mixture was stirred at 50° C. overnight. The mixture was then poured into water, 1 N HCl was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 0-3%).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][NH:4]1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16]>CN(C)C=O>[C:18]([CH2:19][N:5]1[NH:4][C:3](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13])([O:17][CH2:15][CH3:16])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH][nH]c(=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1[nH]c(=O)c2ccccc2c1=O
Yield: 10 %

Procedure:
A mixture of sodium hydride (0.05 g; 0.01 mol; 50% suspension in mineral oil); 2,3-dihydrophthalazine-1,4-dione (1.6 g; 0.01 mol); and ethylbromoacetate (excess) in anhydrous dimethylformamide (50 ml) was refluxed for 24 hours. The dimethylformamide solvent was then evaporated affording a gummy material. This gummy material was purified over column silica gel using chloroform: ethyl acetate (1:1) to obtain the product, 2-(1'-carbethoxymethyl)-2,3-dihydrophthalazine-1,4-dione.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:34])=[CH:8][CH:7]=1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(N(CCCl)CCCl)cc1)Nc1cccc([N+](=O)[O-])c1
Reaction time: 0.71 h

Procedure:
To a stirred mixture of N-mustard amine 18 (7.66 g, 25 mmol) and triethylamine (TEA, (4 mL, 27.5 mmol) in CHCl3 (100 mL) was added a solution of 3-nitrophenyl isocyanate 44a (4.1 g, 25 mmol) in CHCl3 (50 mL) dropwise at room temperature. After being stirred additional 40-45 minutes, the solvent was removed by evaporation under reduced pressure and the solid residue was triturated with saturated aqueous solution of NaHCO3 and then collected by filtration. The solid was washed with water, hexane, and dried. The solid was recrystallized from ethyl acetate to give 1-(4-(bis(2-chloroethyl)amino)phenyl)-3-(3-nitrophenyl)urea (45a), 9.1 g (92%); mp 246-247° C. 1H NMR (DMSO-d6) δ: 3.69-3.71 (8H, m, CH2), 6.71-6.74 (2H, d, J=9.0 Hz, Ar—H), 7.29-7.31 (2H, d, J=8.9 Hz, Ar—H), 7.52-7.56 (1H, t, J=8.1 and 8.2 Hz, Ar—H), 7.69-7.71 (1H, d, J=8.0 Hz, Ar—H), 7.78-7.80 (1H, q, J=8.2 and 1.8 Hz, Ar—H), 8.52 (1H, brs, NH), 8.54-8.55 (1H, d, J=2 Hz, Ar—H), 9.11 (1H, brs, NH).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[P:27]([O:34]CC)([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].[I-].[Na+]>C(#N)C>[CH2:29]([O:28][P:27]([CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)([O:31][CH2:32][CH3:33])=[O:34])[CH3:30]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product from Step C is dissolved in acetonitrile and cooled to 0° C. Triethyl phosphite (1 equivalent) and sodium iodide (1 equivalent) are added, and the reaction stirred at room temperature overnight. The reaction is quenched with ammonium chloride, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([N:36]2[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]2)=[O:35])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([C:34]([N:36]5[CH2:40][CH2:39][C@@H:38]([OH:41])[CH2:37]5)=[O:35])[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C(C1CNC1)N1CC[C@@H](O)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CC[C@@H](O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (75 mg, 0.19 mmol), azetidin-3-yl-((R)-3-hydroxypyrrolidin-1-yl)methanone (65 mg, 0.38 mmol), and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to afford 461 as a white solid (17 mg, 16%). LCMS (Method I): RT 2.34 min, [M+H]+ 546. 1H NMR (400 MHz, CDCl3): δ 7.96-7.95 (1 H, m), 7.73-7.69 (1 H, m), 7.22 (2 H, s), 4.52-4.48 (2 H, m), 4.31 (4 H, s), 3.82-3.82 (8 H, m), 3.59-3.57 (9 H, m), 3.32-3.30 (2 H, m), 1.98-1.97 (2 H, m), 1.40 (3 H, t, J=7.48 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[C:9]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)[CH:7]=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]3[C:9]4[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]5[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=5[F:27])[C:10]=4[N:11]=[C:12]([S:14][CH3:15])[N:13]=3)[CH:7]=2)=[O:38])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Product: CSc1nc(-c2cc(NC(=O)c3ccc(Cl)nc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound was prepared as described in Example 7b from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one and 6-chloro-3-pyridinecarbonyl chloride: LC-MS m/z 550 (M+H)+, 2.63 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]([OH:14])[CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: C=CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5 g (21.81 mmol) of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester are dissolved in 33 ml of THF, placed under argon and cooled to −78° C. 43.62 ml (21.81 mmol) of a 0.5 M 3-butenylmagnesium bromide solution in THF are added dropwise. The mixture is stirred further at room temperature overnight. After TLC check, about 90 ml of a saturated NH4Cl solution are added to the mixture with cooling, the mixture is stirred further overnight and diluted with about 50 ml of water. The phases are separated, and the aqueous phase is extracted a further twice with EA. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue is subjected to flash chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:38][CH:37]=[CH2:36])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: C=CCBr
Product: C=CCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with allyl bromide
Reaction SMILES: Cl.[CH:2]([C:5]1[S:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][C:16]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:15][CH2:14][CH2:13]2)=[O:11])[N:9]=1)([CH3:4])[CH3:3].Br[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][C:16]2([O:15][CH2:14][CH2:13][N:12]([C:10]([C:8]3[N:9]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:6][CH:7]=3)=[O:11])[CH2:17]2)[CH2:22][CH2:21]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cccc(CCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 60 °C

Procedure:
A mixture of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride [Example 27, step a] (13.6 g) and 2-(3-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20), 4217] (13.51 g) and potassium carbonate (21.7 g) in acetonitrile (700 mL) and water (13 mL) was heated at 60° C. for 36 hours. The solvent was decanted off and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography, using 5% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 13.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[NH:7][C:8]2=[O:13])([O-:3])=[O:2].[OH-:15].[Na+].Cl>O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([C:8]([NH2:7])=[O:13])[C:5]=1[C:6]([OH:14])=[O:15])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
Commercially available 4-nitro-isoindole-1,3-dione (1) (25 g, 0.13 mol) was stirred in water (300 mL) at 0° C. Over a few minutes, an aqueous solution of sodium hydroxide (30% w/w, 35 g, 0.26 mol) was added. The mixture was stirred for 1.5 h at 0-5° C. The cold solution was acidified with concentrated HCl (22 mL, 0.26 mol) and the product precipitated as a white solid. After allowing to stand overnight in a refrigerator, the mixture was filtered to afford the title compound (26.3 g, 96%) as a white solid: 1H NMR (300 MHz, DMSO) δ 8.2 (s, 1H), 8.15 (d, 1H), 7.93 (d, 1H), 7.88-7.65 (m, 2H); ESIMS m/z 211 ([M+H]+), m/z 209 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:8][C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=3[F:33])=[N:13][CH:12]=2)=[O:10])[C:4]([CH3:34])=[N:3]1.[H-].[Na+].I[CH2:38][CH3:39].O>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]([CH2:38][CH3:39])[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=3[F:33])=[N:13][CH:12]=2)=[O:10])[C:4]([CH3:34])=[N:3]1
Reactant: Cc1nn(C)cc1CNC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cn(C)nc1C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To a solution of N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (508) (70 mg, 0.143 mmol) in DMF (1.5 mL) was added sodium hydride (60% in mineral oil, 7 mg, 0.172 mmol) and the reaction was stirred for 15 minutes. Iodoethane (13 mL, 0.172 mmol) was added and stirred for 1 hour. Water was added slowly and the reaction was extracted with 1:1 EtOAc:Hexane, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (90-100% EtOAc in hexanes) to afford N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-N-ethyl-1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (519). 1H NMR (400 MHz, CDCl3) δ: 7.33 (s, 1H), 7.18-6.91 (m, 6H), 6.82-6.73 (m, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 3.77 (s, 3H), 3.37 (q, J=7.0, 2H), 2.16-2.06 (m, 3H), 1.25-1.00 (m, 3H). LC-MS ESI m/z; found 518.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)[N:9]=[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[C:15]([NH2:17])[N:16]=[C:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:9]2)[N:12]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, 300 mg (0.814 mmol) of the compound from example 6A were initially charged in pyridine (10 ml), the mixture was cooled to 0° C. and 78 μl (0.814 mmol) of ethyl chloroformate were then added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then concentrated. The residue was separated by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient) and the product fractions were concentrated. This gave 77 mg (21% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Yield: 96.8 %

Procedure:
A mixture of 4-cyano-benzyl bromide (41.8 g, 0.213 mol) and triethyl phosphite (42 mL, 0.244 mol) was stirred in a flask equipped with a Dean-Stark trap at 150° C. for 6 h, then the reaction mixture was submitted to distillation in vacuo to yield 52.2 g (97%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:43][C:33]1[CH:38]=[CH:37][C:36]([S:39]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](CO)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCc1c(OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 15.6 g (50.0 mmole) of [(2S)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol in 100 mL of methylene chloride was added 26.3 mL (0.15 mole) of N,N-diisopropylethylamine, 0.63 g (5 mmole) of 4-dimethyl-aminopyridine and 14.25 g (75.0 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant. Combination of the product fractions and concentration in vacuum gave 18.0 g (77%) of the (R)-enantiomer of the title compound as a white solid, m.p. 76-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][NH2:19])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 21 °C

Procedure:
A solution of bis-(4-chloro-phenyl)-methanone (5.0 g, 19.9 mmol) and hydrazine monohydrate (5 mL, 103 mmol) in ethanol (25 mL) was heated to reflux 18 h, cooled to 21° C., and filtered to afforded the [bis-(4-chloro-phenyl)-methylene]-hydrazine compound as a yellow solid.