Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1cccc2ccccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCCCOc1cccc2ccccc12

Procedure:
A solution of 10.0 g N-[8-(1-naphthyloxy)octyl]phthalimide, prepared as above, and 200 ml of ethanol and 3.2 ml of hydrazine hydrate was refluxed for 18 hours. The solution was evaporated to about 100 ml, and diluted with 200 ml of water, then basified with aqueous potassium hydroxide and extracted with hexane. The extract was washed, dried and evaporated to give the title compound as an oil which was converted to the hydrochloride, mp 90.5°-92°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]#[N:26].O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]#[N:26])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(Oc2cc(Cl)nc(-c3ccccc3)n2)c1
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To 4,6-dichloro-2-phenylpyrimidine (1.5 g, 6.7 mmol) in acetonitrile (20 mL) was added Cs2CO3 (2.4 g, 7.4 mmol) and 3-hydroxy4-(benzyloxy)benzonitrile (1.5 g, 6.5 mmol). After stirring for 24 hours, water was added to the reaction mixture and the resulting solid was collected by suction filtration to give 2.6 g of 3-[(6-chloro-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][C:29]1([CH3:42])[CH3:41])=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:32][CH2:33][NH:28][C:29]([CH3:42])([CH3:41])[CH2:30]4)=[CH:35][N:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNC(C)(C)C4)cn3)nc2n1C1CCCC1
Yield: 28.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.17 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.15 mmol) gave 7-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 25%). MS(ESI) m/z 463.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[C:16]([F:19])([F:18])[F:17])[CH3:2].[H-].[Na+].[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:23](=[O:25])[CH3:24])[C:7]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of (5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (4.90 g, 17.2 mmol) in DMF (25 mL) is added a suspension of 60% NaH in mineral oil (824 mg, 20.6 mmol). The reaction mixture is stirred for 1 h at room temperature. After cooling to 0° C. acetylchloride (1.84 mL, 25.8 mmol) is added dropwise. The resulting reaction mixture is stirred for 1 h at room temperature, quenched with an aqueous saturated NH4Cl solution and partitioned between water and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, cyclohexane/EtOAc 95:5) affords the title compound as a yellow solid (2.89 g, 8.83 mmol, 51%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.75 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.91 (q, J=2.2 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 3.45 (M(C16H16F3NO3)+H2O)+.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@@H:20]([O:23]C(=O)C)[C:19]2=[O:27])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O>CO>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@@H:20]([OH:23])[C:19]2=[O:27])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(N2CC[C@@H](OC(C)=O)C2=O)nc1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1ccc(N2CC[C@@H](O)C2=O)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
453 mg of 2-benzyl-3-methoxymethyloxy-6-[(3R)-3-acetoxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 5 ml of methanol, and two droplets of a 28% methanol solution of sodium methoxide was added thereto under stirring at room temperature, followed by stirring for 30 minutes. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to separation and purification using silica gel column chromatography using 66% ethyl acetate/hexane as an eluent, to give 371 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:18][NH2:19])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: CSc1nc(Cl)c(-c2ccccc2)c(NN)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a cold (ice bath) stirred solution of 25 g (0.09 mole) of 4,6-dichloro-2-methylthio-5-phenylpyrimidine in 250 ml of methanol was added slowly 10 g (0.2 mole) of hydrazine hydrate. After one hour the mixture was allowed to warm to about 20° C., and was then stirred at 20° C. for about 16 hours. The precipitate was separated by filtration to provide 4-chloro-6-hydrazino-2-methylthio-5-phenylpyrimidine. Recrystallization twice from hexanes/cyclohexane provided white crystals, m.p. 134°-135° C. Analysis: Calculated for C11H11ClN4S: %C, 49.5; %H, 4.15; % N, 21.0; Found: %C, 49.4; %H, 4.0; %N, 20.9.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N#CCNC(=O)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)Cl)C(=O)Cc1ccccc1
Yield: 88.3 %

Procedure:
To a stirred mixture of 4.9 g (0.028 mole) N-cyanomethyl phenylacetamide (the product of Example 6) and 5.7 g (0.031 mole) trichloromethylsulfenyl chloride in ml methylene chloride which had been cooled in an ice bath, 3.5 g (0.035 mole) triethylamine in 25 ml methylene chloride were dropped in over 20 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate and stripped to give 8.0 g of a dark brown oil, which failed to crystallize.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[NH:40]1[CH:39]=[C:38]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:42]=[N:41]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc(-c3cn[nH]c3)c2)cn1)N1CCN(C2CCOCC2)C1=O
Temperature: 80 °C
Yield: 49.6 %

Procedure:
A mixture of Example C1 (0.15 g, 0.359 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.077 g, 0.395 mmol), and K2CO3 (0.198 g, 1.436 mmol) in 4:1 dioxane/water (5 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.041 g, 0.036 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, allowed to stand at RT and the resulting solid collected via filtration to afford N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (80 mg, 48%). 1H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1 H), 10.96 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.32 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 8.02 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.32 (d, J=2.4 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 3.91-3.80 (m, 5 H), 3.40 (m, 4 H), 1.71 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 450.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.Cl.[NH2:12][OH:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:12][OH:13]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.7 %

Procedure:
3,4-Dichlorobenzaldehyde (5.25 g) and 2.1 g of hydroxylamine hydrochloride were dissolved in 75 mL of pyridine. The mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was taken up in 100 mL of 1N HCl and extracted 3× with 75 mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a solid. The crude material was triturated in hexane and collected by filtration to yield 5.8 g of the title compound of Step A as a white solid melting at 118-119° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>S(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([O:14][CH3:15])[CH:4]=1)([CH3:13])[CH3:12])[CH3:17]
Reactant: CCNCC
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1I
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C(C)(C)c1ccc(I)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 2-(4-iodo-3-methoxy-phenyl)-2-methyl-propionic acid (326 mg, 0.976 mmol, prepared by saponification of ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate, example 4) in thionyl chloride (5 mL) was heated at reflux for 1 h. It was concentrated to dryness then taken in 5 mL of tetrahydrofuran. Diethylamine (1 mL, 2 mmol, 2M solution in tetrahydrofuran) was added. The reaction mixture was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, IntelliFlash 280, eluting with a gradient of 5-95% ethyl acetate in hexanes) gave N,N-diethyl-2-(4-iodo-3-methoxy-phenyl)-isobutyramide (361.4 mg, 95%) as clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([O-])=O>CO.[Pd]>[N:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:4]=2[NH2:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1OCCN1CCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1OCCN1CCCC1

Procedure:
To a solution of 1-[2-(2-Nitro-4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (1.70 g, 5.59 mmol) in dry MeOH (56 mL) was added Pd/C (10%, 350 mg). H2 gas was bubbled through the solution, which was then stirred vigorously under an atmosphere of H2. After completion of the reaction by LCMS, the mixture was filtered through celite and concentrated to afford the desired product as a yellow/orange oil. MS (M+H)+=275; Calc'd 274.29 for C13H17F3N2O.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:28])[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:30]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI/CI): predicted mass C23H23N5O2, 401.2.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[CH2:8](C(O)=O)[C:9](CC(O)=O)=[O:10]>C(O)(=O)C>[CH3:8][C:9]([CH:6]1[C:1](=[O:3])[O:4][C:5]1=[O:7])=[O:10]
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)C1C(=O)OC1=O
Yield: 86 %

Procedure:
To a solution of 60 ml of acetic acid and 43 ml of acetic anhydride at 0° C., was added slowly 40 g (0.27 mol) of acetonedicarboxylic acid. The mixture was stirred and the temperature was not allowed to rise above 10° C. The acid was dissolved slowly and a pale yellow precipitate formed. After 3 h the product was filtered, washed with 30 ml of glacial acetic acid and 100 ml of benzene. The white powder obtained was dried at high vacuum to afford 30 g of acetonedicarboxylic acid anhydride (yield 86%). Mp 137-138° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])=[O:27])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1cccc2ccccc12
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2cccc3ccccc23)nc(OC)n1

Procedure:
To a suspension of 16 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 400 ml of acetonitrile was added 23.3 g of 1-naphthalenesulfonyl isocyanate dropwise with stirring. The mixture was stirred for 14 hours and the resultant solid product removed by filtration. After washing with ethyl ether the product melted at 171°-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 6 h

Procedure:
To diethyl[(tert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79 mmol) in ethanol (30 ml) was added sodium ethoxide (9.76 ml, 26.2 mmol) followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture was stirred for 6 h, and the solvent was removed in vacuo. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with saturated aqueous brine (1×50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colorless amorphous solid. LC/MS 366.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH:14]([CH3:17])[CH2:15][OH:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH:14]([CH3:17])[CH2:15][OH:16])[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: CC(N)CO
Product: CC(CO)N1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 2-aminopropanol (Aldrich Cat No. 192171). LCMS (M+H)+=270.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:32][CH2:31][C:30]5([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[N:29]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:32][CH2:31][C:30]5([CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]5)[N:29]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCNCC6)CO5)cc34)cc2C)cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC2(CC1)COC(Nc1ccc3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c3c1)=N2

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-en-8-yl)-ethanone is prepared from N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diaza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH3:5][C:6]([N:10]=[C:11]=[S:12])([CH3:9])[CH2:7][CH3:8]>C(O)C>[C:2]([NH:3][C:11]([NH:10][C:6]([CH3:9])([CH3:5])[CH2:7][CH3:8])=[S:12])#[N:1]
Reactant: CCC(C)(C)N=C=S
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: CCC(C)(C)NC(=S)NC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a suspension of monosodium cyanamide (0.64 g, 10 mmol) in absolute ethanol (30 mL), 1,1-dimethylpropylisothiocyanate (1.29 g, 10 mmol) was added slowly at room temperature. Exothermic reaction occurred during addition and near the end of the addition, the initially heterogeneous mixture became a homogeneous solution. It was allowed to stir at room temperature for 2 hours and then heated at 75° C. for 1 hour. The reaction mixture was cooled to room temperature and the solid was filtered. The filtrate solution was concentrated to yield the title A compound (1.6 g) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CN=Cc1ccc(C(C)C)cc1)OC
Yield: 83.6 %

Procedure:
A mixture of 4-isopropyl benzaldehyde (25 g, 183 mmol) and aminoacetaldehyde dimethylacetal (28.9 g, 275 mmol) in toluene (250 ml) was refluxed with azeotropic removal of water for 13 hours. The solvent was removed under vacuum to afford the titled compound as viscous oil (36 g, 83%). TLC-Chloroform/methanol: (95/5): Rf=0.75. 1H-NMR (CDCl3, 400 MHz) δ 1.28 (6H, d), 2.95 (1H, m), 3.44 (6H, s), 3.78 (2H, d), 4.68 (1H, t), 7.28 (2H, d), 7.68 (2H, d), 8.27 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([C:13](=[O:36])[NH:14][C:15]1[N:16]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:17]=[C:18]([C:20]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH3:40]C([O-])=O.[Na+].[BH3-]C#N.[Na+]>CO>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([C:13](=[O:36])[NH:14][C:15]1[N:16]([C:32]([CH3:33])([CH3:35])[CH3:34])[N:17]=[C:18]([C:20]2([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:25][CH2:24][N:23]([CH3:40])[CH2:22][CH2:21]2)[CH:19]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCNCC2)nn1C(C)(C)C
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reaction time: 16 h

Procedure:
A solution of 0.67 g (1.3 mmol) of {1-[2-tert-butyl-5-(4-phenylpiperidin-4-yl)-2H-pyrazol-3-ylcarbamoyl]ethyl}carbamic acid benzyl ester, 0.33 mL (4.0 mmol) of 37% aq. formaldehyde, 0.33 g (4.0 mmol) of NaOAc and 0.27 g (4.3 mmol) of NaCNBH3 in 10 mL of MeOH was stirred at rt. After 16 h, the reaction mixture was concentrated and extracted with water and EtOAc. The organic layer was dried over MgSO4, and concentrated. Purification on silica gel using 4% Et3N-MeOH as eluant afforded {1-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-ylcarbamoyl]ethyl}carbamic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[C:7]=1[CH3:10])=[O:16])[CH3:13]
Reactant: CCC(CC)C(=O)Cl
Reactant: Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(CC)C(=O)c1oc2ccc(F)cc2c1C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (12.0 g) synthesized in Example A67(2), 2-ethylbutyrylchloride (9.58 g) in nitromethane (240 mL) was added aluminum chloride (anhydrous) (12.94 g) at 0° C., and the mixture was stirred for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (15.02 g, 93%) as a yellow oil.