Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:11]1[S:15][CH:14]=[C:13]([C:16]#[N:17])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].S(Cl)(C)(=O)=O.[C:23]([C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1)#[N:24].[I-].[Na+]>C(#N)C.CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C.O>[C:1]([C:3]([C:11]1[S:15][CH:14]=[C:13]([C:16]#[N:17])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:35]1[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][O:29][C:28]2[CH:38]=[CH:39][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH2:37][CH2:36]1)#[N:2]
Reactant: N#Cc1ccc(OCCN2CCNCC2)cc1
Reactant: CC(C)C(C#N)(CCCO)c1cc(C#N)cs1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(C#N)cc2)CC1)c1cc(C#N)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
In acetonitrile (5 ml) was dissolved 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanol (0.13 g). To the mixture were added triethylamine (0.21 ml) and mesyl chloride (0.048 ml), followed by stirring at room temperature for one hour. Water was added thereto, and the mixture was extracted with ethyl acetate and further washed with brine. After drying over anhydrous magnesium sulfate, the mixture was evaporated, to give a pale yellow oil. The resulting oil was dissolved in DMF (2 ml), followed by adding a DMF solution (4 ml) of 1-[2-(4-cyanophenoxy)ethyl]piperazine (0.14 g), triethylamine (0.21 ml) and sodium iodide (0.15 g). After stirring at 60° C. overnight, ethyl acetate was added thereto, and the mixture was washed with water and further brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a pale yellow oil (0.09 g, 33%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]=O>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCC4CCCCC4)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc(CCC3CCCCC3)c3c(n2)CCN(C)C3)cc1
Yield: 10.4 %

Procedure:
4-(2-Cyclohexylethyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (20.0 mg, 10.4%) was synthesised from 4-(2-cyclohexylethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 431.4 (M+H)+
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C=O)C>[CH2:38]([O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][N:13]2[CH2:12][CH2:11][C@@H:10]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:17][CH:18]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(O)cc21)n1cnc(C(N)=O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc2ccn(CC[C@H](CO[Si](C)(C)C(C)(C)C)n3cnc(C(N)=O)c3)c2c1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Under N2, to a solution of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-hydroxyindol-1-yl)-2-butyl]imidazole-4-carboxamide (80 mg, 0.187 mmol) in DMF (5 ml) was added potassium carbonate (38.7 mg, 0.280 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. And then 1-iodobutane (51.5 mg, 0.280 mmol) was added and the resulting mixture was stirred for 24 hours at 60-80° C. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (3 g) chromatography eluting with chloroform/methanol (50:1) to give 1-[(R)-4-(6-butoxyindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (66.3 mg, 73.3%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]=1[S:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=1)[N:7]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[OH:20]
Reactant: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2
Reaction time: 15 h
Yield: 129.3 %

Procedure:
To a suspension of 4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one (100 g) in a mixture of ethyl acetate (2 l) and water (1 l) was added sodium hydrosulfite (200 g) in one batch with mechanical stirring. The orange reaction mixture was stirred for 15 hours under a nitrogen atmosphere. The resulting white reaction mixture was filtered and the precipitate washed with water under a nitrogen atmosphere to prevent air oxidation of the compound. The title compound (130 g) was obtained as a wet material and was used as such in the next step (Step 2). An analytical sample was air dried, m.p. 185° C.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.[CH3:17][NH2:18]>O>[CH3:17][NH:18][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CO2
Reactant: CN
Solvent: O
Product: CNc1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
Add 23.1 gm of 2-chloro-4,6-dihydro-3H[2]benzopyrano[3,4-b]pyridin-3-one to 100 ml of 40% aqueous methylamine and 250 ml of water. Heat the system in a steel bomb at 140° C. for 5 days. Stop the reaction and isolate the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:23]([C:22]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:24][CH3:25]
Reactant: CCOC(=O)CCCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Reaction time: 3 h
Yield: 90.2 %

Procedure:
The method described in Part A of Example 10 was used to treat ethyl 5-(3-aminoquinolin-4-ylamino)pentanoate (26.3 g, 91.5 mmol) with trimethyl orthobutyrate (18.3 mL, 114 mmol) and pyridinium p-toluenesulfonate (0.5 g). The reaction was complete in three hours to provide 28 g of ethyl 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:23][CH:22]=1
Reactant: NCc1ccncc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 10.8 %

Procedure:
the title compound (13 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), C-pyridin-4-ylmethylamine (62 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 401.3 (M+1, 100%). Yield=11%.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH2:1][CH3:2])[C:11]=1[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1c(C(=O)O)ccc(O)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1c(C(=O)O)ccc(OCc2ccccc2)c1C
Reaction time: 0.5 h

Procedure:
2.10 g of 2-ethyl-4-hydroxy-3-methylbenzoic acid (E1) are dissolved in 50 ml of acetone. 3.30 ml of benzyl bromide and 5.10 g of K2CO3 are subsequently added. The reaction suspension is heated under reflux for 18 h overnight, subsequently filtered off with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is dissolved in 40 ml of ethanol, and 40 ml of 2.0 N NaOH solution are added. The mixture is then heated under reflux for 3 h. The clear solution is diluted with 150 ml of water and adjusted to pH 1 using 20% hydrochloric acid. After stirring for 30 min, the precipitate formed is filtered off with suction, rinsed with water and dried at 90° C. in vacuo overnight, giving 2.45 g of the title compound as a beige, amorphous solid having a melting point of 169° C.; MS: 270.0 (M+); TLC: Rf=0.36 (cyclohexane/ethyl acetate 2:1 parts by volume).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>C(OCC)(=O)C>[NH:10]1[C:7]2=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]2[CH:12]=[CH:11]1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]ccc2c1
Yield: 95 %

Procedure:
To a solution of 5-nitro-1H-pyrrolo[2,3-b]pyridine (0.4 g, 2.45 mmol) in ethyl acetate (100 mL) 5% Pd—C (0.3 g) was added and the mixture subdued to hydrogenation (30 psi) in a Parr apparatus. After 4 hours the catalyst was filtered off through celite, the cake was washed with ethyl acetate and then with a mixture of dichloromethane/methanol 4:1. 1H-pyrrolo[2,3-b]pyridin-5-amine (5-aminoazaindole) was obtained in 95% yield (0.31 g, 2.33 mmol).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8]/[C:7]/1=[N:20]\[NH2:21])[CH2:2][CH2:3][CH2:4][CH3:5].[C:22](OCC)(OCC)(OCC)[CH3:23]>>[CH3:22][C:23]1[N:8]2[C:9](=[O:19])[C:10]3[NH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:20][N:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone (0.020 g, 0.14 mmol) and triethyl orthoacetate (2 mL, 10 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by preparative LCMS. The product fractions were collected and lyophilized to yield pure product as white powder. LCMS calculated for C13H15F3N6O: (M+H) 329.1; found: 329.1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:16]2[N:27]=[CH:28][CH:29]=[C:15]2[N:14]=1)[CH2:10][CH2:11][CH3:12].O>COCCOC.O>[Br:8][C:29]1[CH:28]=[N:27][N:16]2[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:14][C:15]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1cc(OCc2ccncc2)n2nccc2n1
Solvent: COCCOC
Solvent: O
Product: CCCCc1cc(OCc2ccncc2)n2ncc(Br)c2n1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
NBS (0.38 g) was added to a solution of 0.5 g of 5-n-butyl-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine in 10 ml of DME-water (3:1) at 0° C. and stirred for 1 hour. The mixture was stirred at room temperature for another 2 hours to allow the reaction to proceed. Some water was added to the reaction mixture, and the crystals precipitated were collected by filtration to provide 0.6 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[C:8]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:14])=[CH:10][C:11]=2[CH3:13])[NH:6][CH2:5]1.I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:23]([N:6]1[C:7]2[C:12](=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[CH:4]([CH2:3][CH2:2][OH:1])[CH2:5]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCI
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CC(CCO)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 70 °C
Reaction time: 10 h
Yield: 13.5 %

Procedure:
N-[3-(2-Hydroxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.6 g) was dissolved in DMF (15 ml) and 1-iodooctane (3.9 g) and K2CO3 (2.3 g) were added, which was followed by stirring at 70° C. for 10 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=5/1-1/2) to give 300 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[C:24](B(O)O)=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[C:25]([O:27][CH3:28])=[N:26][C:21]([O:20][CH3:19])=[N:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ncc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 77.2 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (171 mg, 0.94 mmol) were reacted. After purification the title compound (133 mg, 78% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (bm, 1H), 8.31 (s, 1H), 7.89 (a dd, J=2.3, 7.4 Hz, 1H), 7.75 (m, 2H), 4.06 (s, 3H), 3.92 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.65 (m, 2H). MS APCI, m/z=367, HPLC 2.07 min
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:12]=[CH:13][C:14](=[O:17])[CH:15]=[CH:16]1
Reactant: O=c1ccn(CCCOC2CCCCO2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1ccn(CCCO)cc1
Yield: 99.2 %

Procedure:
A solution of 1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro-4-pyridone (0.75 g, 3.16 mmol) in acetic acid (8 ml), THF (4 ml) and water (4 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation to give 1-(3-hydroxypropyl)-1,4-dihydro-4-pyridone (480 mg, 99%) as an off-white solid. 1H NMR Spectrum: (DMSOd6) 1.9-1.95(m, 2H); 1.97-2.05(m, 2H); 4.0-4.1(m, 2H); 6.91(m, 2H); 8.36(m, 2H) MS-ESI: 154 [MH]+
Reaction SMILES: C([O:4][CH2:5][C:6]([CH:16]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[N:27]=[CH:26]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[C:7]([NH:9][C:10]1[S:11][CH:12]=[N:13][N:14]=1)=[O:8])(=O)C.Cl>CC#N>[F:38][C:35]1[CH:34]=[CH:33][C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:6]([CH2:5][OH:4])([CH3:15])[C:7]([NH:9][C:10]4[S:11][CH:12]=[N:13][N:14]=4)=[O:8])=[CH:31][CH:30]=3)[CH:26]=[N:27]2)=[CH:37][CH:36]=1
Reactant: CC(=O)OCC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Solvent: CC#N
Product: CC(CO)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 7.3 %

Procedure:
Example 155 was prepared from 3-(1,3,4-thiadiazol-2-ylamino)-2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methyl-3-oxopropyl acetate (24 mg, 0.168 mmol) by treating with 1N HCl in CH3CN and heating for 1 hr at reflux. The product was purified by HPLC to give 6 mg of desired product. MS found: (M+H)+=48.
Reaction SMILES: [H-].[Na+].C(O)C.[Cl-].[CH2:7]([O:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][C:14]=1[CH3:39])[CH3:8].[CH3:41][C:42]1[N:43]=[C:44]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[S:45][C:46]=1[CH:47]=O>O>[CH2:7]([O:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([CH:17]=[CH:47][C:46]2[S:45][C:44]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:53][CH:54]=3)=[N:43][C:42]=2[CH3:41])=[CH:15][C:14]=1[CH3:39])[CH3:8]
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc(C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (0.040 g, 60% dispersion in mineral oil) was added to anhydrous ethanol (20 ml) followed by [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride (intermediate 18, 0.45 g) after 10 minutes. After a further 10 minutes 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (intermediate 2, 0.24 g) was added and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was treated with water and then the mixture extracted with chloroform. The chloroform solution was separated with a hydrophobic frit and excess aldehyde removed using 3-[4-(hydrazinosulfonyl)phenyl]propionyl AM resin (0.50 g). The crude product remaining after this treatment was purified by Biotage™ chromatography using a mixture of petroleum ether:ethyl acetate (5:1) as eluent to give the title compound as a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C@H:5]([OH:21])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8].N1C(C)=CC=CC=1C.O([Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C@H:5]([O:21][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of the crude alcohol 12 (2.7 g, 9.1 mmol) in CH2Cl2 (10 mL) under argon, cooled to 0° C., 2,6-lutidine (2.6 mL, 22.7 mmol) and triisopropylsilyl triflate (3.6 mL, 13.6 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h and diluted with CH2Cl2 (25 mL). The organic layer was separated and washed with 10% HCl (50 mL), NaHCO3 (50 mL, sat) and NaCl (50 mL, sat), dried (Na2SO4), filtered and concentrated. The crude oil was purified by column chromatography (silica gel, diethyl ether/hexanes 2:98 to 15:85) to yield 13 (2.9 g, 70%) as colorless oil. 1H-NMR (500 MHz, CDCl3): 0.88 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H), 1.01-1.07 (m, 2H), 1.97-2.04 (m, 1H), 2.53 (dd, J=15.3 and 4.7 Hz, 1H), 2.60 (dd, J=15.2 and 7.5 Hz, 1H), 3.57 (s, 3H), 3.59-3.65 (m, 1H), 4.34-4.40 (m, 1H), 4.78 (d, J=10.3 Hz, 1H), 5.06-5.09 (m, 2H), 7.27-7.35 (m, 5H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/[CH:11]=O)=[CH:7]/N(C)C)=[O:5].Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na]>CCO>[C:15]1([C:14]2[N:22]=[CH:11][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:7][N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C(C=O)=C/N(C)C
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1
Yield: 76.2 %

Procedure:
A solution of ethyl 3-N,N-dimethylamino-2-formylacrylate (4.0 g, 23 mmol) (Arnold, Coll. Czech. Chem. Commun. 26:3051, 1961), benzamidine hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 mL) was heated at reflux for 1 h. The solution was filtered and concentrated and the residue partitioned between EtOAc and dilute HCl (10%). The organic layer was dried (Na2SO4), and concentrated to give ethyl 2-phenylpyrimidine-5-carboxylate (4.0 g, 75% yield); m.p. >220° C. (dec.).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]=[O:41])[C:16]=12>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]([C:5]#[N:6])[OH:41])[C:16]=12
Reactant: COc1c(C)cnc(Cn2nc(CC=O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc(CC(O)C#N)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 16 h
Yield: 94 %

Procedure:
Trimethylsilyl cyanide (0.219 mL) and triethylamine (0.198 mL) were added to a mixture composed of the above di-tert-butyl {4-chloro-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (796 mg) and dichloromethane (10 mL) under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for 16 hours. Chloroform (80 mL) and a 0.5 N hydrochloric acid solution (100 mL) were added to the reaction mixture, followed by separation. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (20 mL). A 1 N hydrochloric acid solution (10 mL) was added and the mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate solution (80 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (788 mg, 94%). The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[CH3:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: Cc1cccc(C(=O)CBr)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)CSC#N)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of 2-bromo-1-(3-methylphenyl)ethanone (3.03 g, 14.2 mmol) and potassium thiocyanate (1.45 g, 14.2 mmol) in ethanol (30 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (30 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 2.29 mg (84.2%) of the desired product as a solid.