Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(S)C.C([O:30]/[N:31]=[C:32](/[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)\[C:33]([NH:35][CH:36]1[C:51](=[O:52])[N:38]2[C:39]([C:48]([OH:50])=[O:49])=[C:40]([CH2:43][O:44][C:45](=[O:47])[NH2:46])[CH2:41][S:42][C@H:37]12)=[O:34])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:30]/[N:31]=[C:32](/[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)\[C:33]([NH:35][CH:36]1[C:51](=[O:52])[N:38]2[C:39]([C:48]([OH:50])=[O:49])=[C:40]([CH2:43][O:44][C:45](=[O:47])[NH2:46])[CH2:41][S:42][C@H:37]12)=[O:34]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3cscn3)[C@H]2SC1
Solvent: CCS
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\O)c3cscn3)[C@H]2SC1
Reaction time: 1.83 h
Yield: 78.3 %

Procedure:
To a stirring mixture of trifluoroacetic acid (3 ml) and ethyl mercaptan (1 ml) was added 7-[(Z)-2-trityloxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (110 mg). The stirring was continued for 110 min at room temperature. The reaction mixture was concentrated to dryness under reduced pressure at room temperature. Resulting crystals were washed with diethyl ether, and dried in vacuo over calcium chloride to give the title compound (55 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:11])[CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([Mg]Br)[CH3:13].CCOCC.C(OCC)(=O)C>O1CCCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH:9]2[CH2:13][CH2:12]2)[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: CN(C=O)c1cccc(Br)c1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(c1cccc(Br)c1)C1CC1
Temperature: 25 °C
Yield: 15 %

Procedure:
A stirred, cooled (0° C.) solution of N-(3-bromo-phenyl)-N-methyl-formamide (Intermediate 112, 2.6 g, 9.7 mmol) and titanium tetra-iso-propoxide (3.9 mL, 10.67 mmol) in tetrahydrofuran (40 mL) was treated with a 3M solution of ethyl magnesium bromide in ether (8.08 mL, 24.25 mmol) under argon and the resulting reaction mixture was allowed to warm to ambient temperature gradually and refluxed at 55° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution, filtered over celite and the aqueous phase was extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil. Flash column chromatography over silica gel (230–400 mesh) using 1.5% ethyl acetate in hexane as the eluent afforded the title compound (0.321 g, 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[N:11]1(S(O)(=O)=O)[CH2:15][CH2:14][N:13]=[CH:12]1>C(O)C(C)C.ClCCl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]3[NH:13][CH2:14][CH2:15][N:11]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=S(=O)(O)N1C=NCC1
Solvent: ClCCl
Solvent: CC(C)CO
Product: c1cc2c(cc1NC1=NCCN1)CCC2
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 5-aminoindan (200 mg, 1.50 mmol) and 2-imidazolinesulfonic acid (450 mg, 3.00 mmol) in isobutyl alcohol (5 mL) was heated at reflux for 3 h and then stirred overnight. The solvent was removed to give a dark oil. It was flash chromatographed over silica gel (EtOAc:MeOH:Et3N=6:2:1) to afford a yellow solid. The solid was redissolved in dichloromethane, and washed with saturated aqueous Na2CO3. The organic layer was cried and concentrated to give yellow crystals (220 mg, 73% yield): mp 41°-42° C.; EIMS m/z=201 (M+). Anal. Calcd. for C12H15N3 4/5H2O: C, 66.82; H, 7.74; N, 19.48. Found: C, 6.77; H, 7.31; N, 19.24.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7](=[O:14])[CH2:6][CH2:5]2.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:3]1[C:2]([O:1][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[C:11]([CH3:12])[C:10]([CH3:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:14])[O:8]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(=O)O2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C(C)C)(C(C)C)C(C)C)CCC(=O)O2
Yield: 58.3 %

Procedure:
A solution of 6-hydroxy-5,7,8-trimethyl-chroman-2-one (1.22 g), triisopropylsilyl chloride (1.71 g) and imidazole (806 mg, 11.84 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for two days. The solution was diluted with ethyl acetate, washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate) gave 1.25 g of 5,7,8-trimethyl-6-triisopropylsilanyloxy-chroman-2-one.
Reaction SMILES: [C:1]([CH2:3][NH:4][CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2].IC.[C:22](=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH3:22][N:4]([CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:1]#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#CCNCCC(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CI
Product: CN(CC#N)CCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A mixture of 0.72 g (2.9 mmol) N-cyanomethyl-3,3-diphenylpropylamine (from step 1), 0.49 g (3.4 mmol) iodomethane and 1.6 g potassium carbonate in 5 ml acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, the solvent evaporated, and the residue chromatographed on silica gel column with 20% ethyl acetate in hexanes to give 0.33 g (yield 43%) N-methyl-N-cyanomethyl-3,3-diphenylpropylamine as an oil which solidified on standing. 1H NMR ((CDCl3, 300 MHz) 7.30-7.10 (m, 10 H), 4.02 (t, 1 H, 3.47 (s, 3 H), 2.38 (t, 2 H), 2.32 (s, 3H), 2.19 (dt, 2H);
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[CH:5]2.[N:15]1C2C(=CC=CC=2)C=C[CH:16]=1>>[CH3:14][C:3]1[C:2]([C:16]#[N:15])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: Cc1c(Br)ccc2[nH]c(C(=O)O)cc12
Reactant: c1ccc2ncccc2c1
Product: Cc1c(C#N)ccc2[nH]ccc12
Temperature: 230 °C

Procedure:
4.71 g (18.5 mmol) of 5-bromo-4-methyl-1H-indole-2-carboxylic acid and 5.03 g (56.2 mmol) of cuprous cyanide were dissolved in 35 ml of quinoline and the solution heated at 230° C. for 90 minutes. The reaction mixture was then cooled down to ambient temperature and poured onto crashed ice. The pH was adjusted to pH 2-3 and the mixture subsequently extracted 3 times with ether. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a crude product which was purified by chromatography (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 2.36 g of 4-methyl-1H-indole-5-carbonitrile as light brown solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[CH:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoic acid 20 mg of white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([S:19]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([S:19]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(CS(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)Cc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g (2.7 mmol) of the above methyl ester (b), 40 ml of THF and 40 ml of methanolic sodium hydroxide solution (2N) were introduced into a round-bottomed flask and the mixture was stirred at room temperature for eight hours. The reaction medium was evaporated to dryness and the residue was taken up in water, acidified to pH 1 and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated from hexane, filtered and dried. 900 mg (78%) of the expected acid, having a melting point of 164°-5° C., were recovered.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=O.[NH3:34].CO>>[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)(=[O:2])[NH2:34]
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: N
Solvent: CO
Product: Cc1cc(Nc2cc(C(N)=O)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Yield: 93 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (200 mg, 0.45 mmol) and a solution of 7N ammonia in methanol (7 ml, 49 mmol) was heated at 65° C. in a sealed vessel under microwave irradiation for 1 hour. The reaction mixture was evaporated, dissolved in methanol and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue triturated with diethylether. The resulting solid was collected by filtration to give the title compound (180.0 mg, 93%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10]3)[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
(R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.16 mmol, 50 mg), prepared as in Example 3 (step e) above was dissolved in tetrahydrofuran (2 mL) and triethylamine (0.299 mmol, 42 μL, 30 mg) followed by methanesulfonyl chloride (0.16 mmol, 18.4 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl. (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (R)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)methanesulfonamide (18.3 mg, 0.047 mmol, 29.2%) MS (ESI): m/z [M+H]+ 390.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:19]2[CH2:21][CH2:20]2)[CH2:9][CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:4]([CH:22]=O)[CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH:19]3[CH2:20][CH2:21]3)[CH2:9][CH2:10][C:11]([C:12]([OH:14])=[O:13])=[CH:22][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCCN(c1ccc(Br)cc1C=O)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Br)ccc2N(C2CC2)CC1
Temperature: 55 °C
Yield: 54.6 %

Procedure:
In THF (10 ml) was dissolved t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (1 g). To the solution was added potassium t-butoxide (0.59 g), and the mixture was heated at 55° C. for 1.5 hours. The solvent was evaporated, which was extracted with water. The aqueous layer was washed with ethyl acetate, and neutralized by addition of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-bromo-1-cyclopropyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.44 g) as yellow crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)cc1F
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2)cc1F
Yield: 61 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-bromo-2-fluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VI, and 3-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 61%.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:16]([CH3:18])[C:12]1[CH:11]=[C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:27]4[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=4)[N:9]3[N:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: CN(C)c1cccc(-c2nn3c(I)cnc3s2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C)c1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C
Yield: 16.4 %

Procedure:
A mixture of [3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-phenyl]-dimethyl-amine (0.084 g, 0.226 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.098 g, 0.339 mmol, 1.5 eq), 2M aq Na2CO3 (1 mL) and PdCl2(PPh3)2 (0.032 g, 0.045 mmol, 0.2 eq) was heated at 110° C. for 24 h. The solvent was removed in vacuo and the residue was redissolved in DCM/water (150 mL) and extracted with DCM (2×80 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated from MeOH and filtered off. The solid was purified by column chromatography (0-5% MeOH in DCM) to give the desired product (15 mg, 16%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.97 min, [M+H]+ m/z 405.1; 1H NMR (300 MHz, DMSO) δ 8.86 (d, J=1.8 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.20 (m, 2H), 6.99 (dd, J=9.1, 2.0 Hz, 1H), 6.75 (s, 2H), 3.00 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[N:7]12[CH2:14][CH2:13][C:10]([C:15]([O:17]CC)=O)([CH2:11][CH2:12]1)[CH2:9][CH2:8]2>C1COCC1>[N:7]12[CH2:8][CH2:9][C:10]([C:15]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[OH:17])([CH2:11][CH2:12]1)[CH2:13][CH2:14]2
Reactant: [Li]c1cccs1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 2-thienyllithium (1.0M in THF, 9.10 mL, 9.10 mmol) was chilled down to −30° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.4196 g, 2.289 mmol) in THF (8 mL) was slowly added to the reaction mixture over 20 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with water and then evaporated to dryness. H2O and DCM were added, causing a light brown solid to crash out. This solid was filtered off to give the title compound (0.4161 g, 59.5%). EI-MS m/z 306 (M+H+) Rt (1.35 min).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([NH:13][C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[N:18]=[CH:17]3)=[N:6][CH:7]=[N:8]2.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][C:5]3[C:4]4[C:3]([OH:2])=[CH:12][CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][N:6]=3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
A mixture of 5-methoxy-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (10.1 g, 27.4 mmol) and pyridine hydrochloride (15.8 g, 137 mmol) in pyridine (150 ml) was heated at reflux for 3 hours. After cooling and evaporation of the solvents, the residue was triturated in 5% aqueous sodium bicarbonate and the resulting mixture was stirred for 30 minutes. The yellowish precipitate was filtered, washed with water and ether, and dried over P2O5 under high vacuum to give 4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-ol as a solid (10.1 g, 100%); NMR spectrum 5.76 (s, 2H), 6.67 (m, 2H), 6.96 (d, 1H), 7.29 (m, 1H), 7.42 (m, 1H), 7.52 (dd, 1H), 7.74-7.66 (m, 2H), 8.13 (s, 1H), 8.33 (s, 2H), 8.52 (d, 1H); Mass spectrum MH+ 369.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:11]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH:22]([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[NH2:18])[CH:12]([CH3:14])[CH3:13].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:11]([C:15]1[CH:16]=[C:17]([NH:18][C:8]([C:3]2[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=2)=[O:10])[CH:19]=[CH:20][C:21]=1[CH:22]([C:27]([F:28])([F:29])[F:30])[C:23]([F:24])([F:25])[F:26])[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1nccnc1C(=O)O
Reactant: CC(C)Cc1cc(N)ccc1C(C(F)(F)F)C(F)(F)F
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nccnc1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Yield: 69.2 %

Procedure:
3-Methylpyrazine-2-carboxylic acid (138 mg, 1 mmol), 3-isobutyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (299 mg, 1 mmol), 2-chloro-1-methylpyridinium iodide (255 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in tetrahydrofuran (10 ml) and refluxed under heating for 3 hours. The reaction solution was diluted with ethyl acetate, followed by washing with water. The organic layer was dried over magnesium sulfate anhydride, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 290 mg of the desired compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:11]=[C:12](O)[C:13]2[S:19][CH2:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([Cl:23])[C:13]2[S:19][CH2:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1nc(COCc2ccccc2)nc2c1SCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(COCc2ccccc2)nc2c1SCCC2

Procedure:
The title compound was prepared following substantially the same procedure described in Example 1, Step B using the title compound from Step A hereof and phosphorus oxychloride. The procedure gave 0.8 gm of product as a brown solid which was used in Step C without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[CH:9]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([O:17][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[CH:12][C:11]=1[C:14](=[O:16])[CH3:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)cc1OCc1ccccc1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
Potassium carbonate (4.02 g, 29.10 mmol) was added to a solution of 4′-fluoro-2′-hydroxyacetophenone (2.0 mL, 2.56 g, 16.60 mmol) in DMF (15 mL). Benzyl bromide (2.07 mL, 2.98 g, 17.50 mmol) was added dropwise over 5 minutes at room temperature, and the mixture stirred for 18 h. The mixture was poured into hydrochloric acid (1.0 M in H2O; 200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo. Pure 2′-(benzyloxy)-4′-fluoroacetophenone (3.94 g, 97%) was obtained as a white powder after trituration with hexane. Rf 0.44 (9:1 hexane:EtOAc); δH (CDCl3) 7.82 (1H, dd, J=8.6 and 7.0 Hz), 7.43-7.38 (5H, m), 6.75-6.69 (2H, m), 5.13 (2H, s), 2.56 (3H, d, J=3.2 Hz); LCMS retention time 2.68 min, M+H+ 245.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:16]=[C:15]([CH2:17]O)[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3cc(CO)sc3C2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CC2Cc3cc(C)sc3C2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of step b) was dissolved in EtOAc (50 ml) and 10% Pd/C (1 gram) was added. The flask was evacuated and purged four times with N2 and then a balloon of H2 was added and the reaction was stirred for 24 hours at room temperature. Next, the mixture was passed through a pad of celite and the solvent was concentrated providing the subtitled product that was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[OH-].[K+].[C:13](#[N:16])[CH:14]=[CH2:15]>O1CCOCC1>[C:13]([CH2:14][CH2:15][O:1][CH2:2][C:3]([CH2:8][O:9][CH2:15][CH2:14][C:13]#[N:16])([CH2:6][O:7][CH2:15][CH2:14][C:13]#[N:16])[CH2:4][O:5][CH2:15][CH2:14][C:13]#[N:16])#[N:16]
Reactant: C=CC#N
Reactant: OCC(CO)(CO)CO
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCCOCC(COCCC#N)(COCCC#N)COCCC#N
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Pentaerythritol (6.84 g, 50 mmol) was dissolved in 20 ml dioxane and 2 ml water and mixed up with 40% aqueous potassium hydroxide solution (w/v, 1 ml). After cooling to 0° C. in an ice bath, acrylonitrile (16.2 g, 300 mmol) was added and the mixture stirred for 48 h at room temperature. Solvents were evaporated, the remaining oil was diluted in 100 ml dichloromethane and washed with 10% aqueous sodium chloride solution (w/v, 50 ml). After re-extraction of the aqueous layer with dichloromethane (2×25 ml), the combined organic layers were dried over sodium sulfate and intensively evaporated. The nitrile was obtained as a colorless syrup: yield: 14.32 g (41 mmol, 82%). 1H-NMR (400 MHz, CDCl3) δ 2.60 (t, 8 H,—CH2CN), 3.50 (s, 8 H, —CqCH2O—), 3.65 (t, 8 H, —OCH2—). 13C-NMR (100 MHz, CDCl3) δ 18.86 (—CH2CN), 45.68 (Cq), 65.88 (—OCH2—), 68.82 (CqCH2O—), 118.22 (CN).