Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Si:34]([O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Si:34]([O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4[C:20](=[O:32])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[O:18])=[C:11]([F:33])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:46]=[N:45]1)([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 70 °C
Yield: 87.6 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.101 g, 0.214 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.098 g, 0.278 mmol) and K2CO3 (0.089 g, 0.642 mmol) in dioxane (2 mL) and H2O (0.333 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.012 g, 10.70 μmol), sparged with Ar again, and heated to 70° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (124 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H); 8.58-8.59 (m, 2H); 8.39 (d, J=5.7 Hz, 1H); 8.23 (s, 1H); 8.16 (dd, J=6.6, 2.2 Hz, 1H); 8.01 (s, 1H); 7.60-7.62 (m, 3H); 7.43 (m, 2H); 7.19 (d, J=2.5 Hz, 1H); 6.43-6.75 (m, 2H); 4.18 (t, J=5.1 Hz, 2H); 3.89 (t, J=5.2 Hz, 2H); 0.75 (s, 9H); −0.12 (s, 6H); MS (ESI) m/z: 662.3 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([NH:1][CH:2]1[CH:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC1O
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl trans-3-amino-4-hydroxypyrrolidine-1-carboxylate (500 mg, the compound of Step A, Intermediate 15), in dichloromethane (20 mL) at 0° C. was added acetic anhydride (0.24 mL) and stirring continued for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate (40 mL), extracted with dichlomethane (4×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound which was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23]([CH3:30])=[N:22]1>>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[O:28])[C:23]([CH3:30])=[N:22]1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1nn(C)c(C)c1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 69 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,3,5-trimethyl-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 75°-77° C., in a 69% yield.
Reaction SMILES: CN(C)C=O.[OH:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:23][O:22][C:20]([CH2:19][O:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])=[O:21]
Reactant: COC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 50 ml of dry N,N-dimethylformamide are added 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate, followed by addition of 8.5 g of potassium carbonate. The mixture is stirred at room temperature for 2 days and, then, poured into 400 ml of water. The resulting crystalline precipitate is recovered by filtration, washed with water, hexane and ether in this order to give colorless needles of N-methoxycarbonylmethoxyphthalimide, m.p. 137°-142° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].CCN(C(C)C)C(C)C.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C(Cl)Cl>[CH3:9][C:3]1[C:2]2[NH:1][C:24](=[O:25])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(O)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25.0 g (200 mmol) 2-amino-m-cresol and 70.4 mL (400 mmol) DIPEA were placed in 1.0 L DCM and cooled to 0° C. To this a solution of 38.0 g (227 mmol) CDI was added dropwise over 30 min. The mixture was stirred for 30 min at 0° C., then stirred overnight at RT. After evaporation of the reaction mixture i. vac. down to half the volume, the aqueous phase was washed with water (2×250 mL), 1M aqueous potassium hydrogen sulphate solution (1×250 mL) and again water (1×250 mL). The organic phase was evaporated down i. vac. The crude product left as a solid was triturated with a mixture of diethyl ether and PE, the precipitated solid was suction filtered, washed with PE and dried i. vac.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18]>>[NH2:2][C:1]1[N:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[N:18]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1ccc(C(=O)O)cc1
Product: Cc1ccc(-c2nn(-c3ccc(C(=O)O)cc3)c(N)c2C(N)=O)cc1
Yield: 73.9 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)-acrylamide (464 mg, 2.0 mmol) and 4-hydrazinobenzoic acid (334 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was purified by column chromatography (SiO2, 5-10% methanol +2% acetic acid in CH2Cl2) and by trituration with methanol to give the title compound as a light yellow solid (497 mg) m.p. >310° dec. δH (d6DMSO) 8.06 (2H, d, J 8.7 Hz), 7.75 (2H, d, J 8.6 Hz), 7.48 (2H, d, J 8.1 Hz), 7.29 (2H, d, J 8.0 Hz), 6.63 (2H, br s) and 2.36 (3H, s), carboxyl proton and amino protons not observed.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([CH2:26][NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=1
Reactant: NC1c2ccccc2CCC1Cc1ccccc1
Reactant: COC(=O)c1cccc(C=O)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN[C@@H]2c3ccccc3CC[C@H]2Cc2ccccc2)c1
Yield: 28 %

Procedure:
In a procedure similar to preparation C, the title compound was prepared from 1-amino-2-benzyltetralin and 3-carbomethoxybenzaldehyde. The trans isomer was isolated as an oil in 28% yield following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]2)=[O:13])=[CH:10][CH:9]=1.C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.CCN(C(C1C=CC=C(C)C=1)=O)CC>CN(C=O)C>[CH:1]1([NH:6][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:28]=[CH:29][CH:30]=[C:15]([NH:14][C:12](=[O:13])[C:11]4[CH:31]=[CH:32][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH:16]=3)[CH2:24][CH2:23]2)=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)c1)c1ccc(Cl)cc1
Reactant: NC1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCC3)CC2)c1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1-Cyclopentylamine (10.7 mg, 0.124 mmol) is added to a solution of [3-(4-chloro-benzoylamino)-benzyl]-piperidine-4-carboxylic acid (35.4 mg, 0.095 mmol) in DMF (0.5 mL). The resulting solution is treated with a solution of HOAT (15.5 mg, 0.114 mmol) in DMF (0.5 mL) followed by si-DCC (200 mg, 0.95 mmol/g, 0.19 mmol), and DIPEA (0.033 mL, 0.19 mmol). The mixture is stirred at 50° C. overnight. PI-DETA (7.99 mmol/g, 0.3 mmol, 37 mg) is added to the solution in order to scavenge the acid, PI-NCO (2.24 mmol/g, 0.3 mmol, 130 mg) is added to scavenge the amine in excess and the mixture is stirred for 1 h. The resin is filtered and washed with a mixture of MeOH/DCM 1:1, (4×1 mL). The resulting solution is evaporated under HV. The title compound is obtained by prep. HPLC F as a colourless powder: LC-MS A: tR=1.21 min; [M+H]+=440.1.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])[CH3:3].O.[NH2:24][NH2:25].O>C(O)C>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][C:10]([NH:24][NH2:25])=[O:11])([CH3:4])[CH3:3]
Reactant: CCOC(=O)COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Yield: 88.1 %

Procedure:
A solution of ethyl [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]acetate (2.5 g, 8.1 mmol) and hydrazine monohydrate (1.2 mL, 24.3 mmol) in ethanol (40 mL) is heated at 65°-75° C. for 8 hours. The reaction mixture is cooled and poured into 500 mL of water. The solids are filtered and washed twice with water. The white solid is dried overnight at 50° C. in vacuo to give 2.1 g (87%) of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]-acetic acid hydrazide; mp 141.0°-142.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CC(C)C(=O)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C(C)C
Yield: 27.5 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with isobutyryl chloride (0.41 mL, 3.9 mmol) to provide 0.34 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropanamide as an off white solid, m.p. 155.4-156.3° C. Analysis: Calculated for C20H27N5O.0.75 H2O: % C, 65.46; % H, 7.83; % N, 19.08. Found: % C, 65.84; % H, 7.87; % N, 18.73.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([C:13]#[N:14])=[C:4]([CH3:15])[N:3]=1.[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].O>C(O)C>[C:13]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:20][CH:16]([CH3:17])[CH2:18][CH3:19])=[N:3][C:4]=1[CH3:15])#[N:14]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C#N)c(C)nc1NC(C)CC

Procedure:
22.4 g of 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (1 mol) of Example 1(b) are treated in 100 ml of ethanol with 15 g sec. butylamine at reflux temperature with stirring. After the addition of the amine is completed, the solution is poured into 200 ml of cold water, and the amino compound is filtered off. Yield 22 g (84%); m.p. 55°-57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH2:12][CH:11]([C:13](=O)[CH3:14])[O:10][N:9]2[CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH2:12][CH:11]([C:13](=[N:24][OH:25])[CH3:14])[O:10][N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)C1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 25 °C
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, a solution of 3.00 g (0.00938 mol) of 1-[3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidin-5-yl]ethanone [isomer A (3, R1 =4-Cl, R2 =CH3)], 0.69 g (0.010 mol) of hydroxylamine hydrochloride and 0.60 g (0.015 mol) of sodium hydroxide in 75 ml of ethanol is refluxed for 1 hour, cooled to ambient temperature, neutralized with 0.1N hydrochloric acid, and extracted with chloroform (2×50 ml). The combined organic extract is washed with 50 ml of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a white solid. Crystallization from ethanol gives 1.57 g (50%) of compound 4, melting point 214°-216° C. (ethanol). Anal. Calcd. for C16H19ClN4O2 : C, 57.40; H, 5.72; Cl, 10.59; N, 16.73. Found: C, 57.24; H, 5.80; Cl, 10.70; N, 16.62.
Reaction SMILES: [CH2:1]([C:3]1([OH:36])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:35])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][C:26]([OH:28])=O)=[C:14]2[CH:31]=[CH:32][CH:33]=[CH:34][C:13]2=[N:12][C:11]3=1)[CH3:2].Cl.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC.C(N(C(C)C)CC)(C)C>>[CH2:1]([C:3]1([OH:36])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:35])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][C:26]([N:39]([CH3:40])[CH3:38])=[O:28])=[C:14]2[CH:31]=[CH:32][CH:33]=[CH:34][C:13]2=[N:12][C:11]3=1)[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC(=O)O
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Compound 47 (1 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.099 mmol) and 1-hydroxybenzotriazole (catalytic amount). Dimethylamine (0.04 ml, M=2 in tetrahydrofuran) and diisopropylethylamine (0.1 ml) were added to the above solution at ice bath. The resulted solution was stirred at room temperature for 3 days. The reaction was quenched with 1 N HCl and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtrated through silica gel, and concentrated by rotary evaporation. Purification by radial preparative-layer chromatography (ethyl acetate/hexanes 50/50 to methanol/chloroform 2/98) provided 12 mg of Compound 48 as a yellow solid.
Reaction SMILES: Cl.CNC.C=O.[C:7]([O:10][C:11](=O)[CH3:12])(=O)[CH3:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[N:27]3[N:28]=[CH:29]C=[C:26]3[N:25]=[CH:24][CH:23]=2)[CH:17]=1>>[CH2:7]([O:10][CH2:11][C:12]1[CH:29]=[N:28][N:27]2[C:22]([C:18]3[CH:17]=[C:16]([C:15]([F:32])([F:14])[F:31])[CH:21]=[CH:20][CH:19]=3)=[CH:23][CH:24]=[N:25][C:26]=12)[CH3:8]
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: CNC
Agent: Cl
Product: CCOCc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 2.15 g. of dimethylamine hydrochloride, 1.5 ml. of 37% formalin, and 10.5 ml. of acetic anhydride is swirled and heated gently until the reaction mixture becomes homogeneous. To the mixture is added 2.63 g. of 7-(α,α,α-trifluoro-m-tolyl) pyrazolo[1,5-a]pyrimidine and the reaction mixture is heated for 2 hours on a steam bath. The reaction mixture is evaporated to dryness and acetone is added and briefly refluxed and evaporated to dryness again. Water is added and the mixture extracted with methylene chloride. The residue, on evaporation of the solvent, when recrystallized from ethanol gave the product, m.p. 110°-111° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[I:11]I>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: II
Reactant: CCOC(=O)c1cc[nH]n1
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 0 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A suspension of Intermediate 74a (5.00 g, 35.7 mmol) in acetonitrile (90 mL) was treated with iodine (9.10 g, 35.7 mmol) then ceric ammonium nitrate (19.6 g, 35.7 mmol) and the mixture was stirred at RT overnight. Another portion of iodine (2.28 g, 9.0 mmol) was added and the mixture was stirred for a further 24 h then treated with ice-cold aqueous sodium hydrogensulphite solution (5%, 100 mL). The mixture was filtered through Celite rinsing with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting solid was triturated with ether/cyclohexane, filtered off, washed with cyclohexane and dried at 50° C. in vacuo to give the title compound (3.70 g, 39%). LCMS (Method 3): Rt 2.88 min, m/z 267 [MH+](weak).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][O:7][CH2:8][C:9](=[O:16])[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>CCOCC>[CH:1]1([C:9]([OH:16])([C:10]#[C:11][Si:12]([CH3:13])([CH3:15])[CH3:14])[CH2:8][O:7][CH3:6])[CH2:3][CH2:2]1
Reactant: COCC(=O)C#C[Si](C)(C)C
Reactant: Br[Mg]C1CC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCC(O)(C#C[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
52.85 ml of 0.5 M cyclopropylmagnesium bromide (26.43 mmol, Aldrich) are added to a solution of 3 g of 1-methoxy-4-(trimethylsilyl)but-3-yn-2-one (17.62 mmol) in 160 ml of ether. The mixture is stirred at ambient temperature overnight and is then cooled with a water/ice bath and a solution of NH4Claq and ethyl acetate is added. The mixture is extracted 3 times with ethyl acetate and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The oily residue is purified by silica column chromatography, elution being carried out with a cyclohexane:ethyl acetate gradient, 100:0 to 80:20, so as to obtain 1.9 g of (±)-2-cyclopropyl-1-methoxy-4-(trimethylsilyl)but-3-yn-2-ol in the form of an oil, with a yield of 51%.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][N:15]1[C:23]([C:24]2[N:25]([CH3:35])[CH:26]=[C:27]([C:29](=O)[C:30]([F:33])([F:32])[F:31])[CH:28]=2)=[C:22]2[C:17]([N:18]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:19](=[O:38])[N:20]([CH3:37])[C:21]2=[O:36])=[N:16]1.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][N:15]1[C:23]([C:24]2[N:25]([CH3:35])[CH:26]=[C:27](/[C:29](=[N:2]/[OH:3])/[C:30]([F:33])([F:32])[F:31])[CH:28]=2)=[C:22]2[C:17]([N:18]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:19](=[O:38])[N:20]([CH3:37])[C:21]2=[O:36])=[N:16]1
Reactant: NO
Reactant: Cn1cc(C(=O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cn1cc(/C(=N/O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.2 %

Procedure:
Hydroxylamine hydrochloride (0.062 g) was added to a solution of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-3-[1-methyl-4-(trifluoroacetyl)-1H-pyrrol-2-yl]-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.05 g) and triethylamine (0.063 ml) in dimethylacetamide (5 ml) and the mixture heated at 80° C. for 2 hours. Additional hydroxylamine hydrochloride (0.062 g) was added and the reaction continued at 80° C. for another 3 hours. Cooled, concentrated, and the crude residue purified on preparative HPLC to give the title compound (0.015 g). Mass: 574.17 (M+H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1=[S:23].[Cl-].CC=[N+]=CC.[CH3:30][N:31]([CH:33]=O)[CH3:32]>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1=[S:23]
Reactant: CCOC(=O)CCn1ccn(C2CCc3ccccc3C2)c1=S
Reactant: CN(C)C=O
Agent: CC=[N+]=CC
Agent: [Cl-]
Product: CCOC(=O)CCn1cc(CN(C)C)n(C2CCc3ccccc3C2)c1=S
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl]propionate (0.5. g, 1.5 mmol), prepared as in Example 34, and N,N-dimethylmethyleneammonium chloride (0.17 g, 1.8 mmol) in 7 mL of DMF was heated at 80° C. under nitrogen for 16 hours. The mixture then was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried (NaSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane to give ethyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylaminomethyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl]-propionate (277 mg, 0.7 mmol), m.p. 128°-130° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH:19](O)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].[BH3-]C#N.[Na+]>CO>[C:22]1([CH:20]([OH:21])[CH2:19][NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1ccccc1)C(O)O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.4–7.25 (m, 5H), 7.0–6.95 (d, 2H), 6.63–6.60 (d, 2H), 4.85–4.79 (dd, 1H), 3.3–3.21 (t, 2H),3.2–3.15 (m, 2H), 2.64–2.5 (t, 2H), 1.42 (s, 9H).