Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N+:17]([O-])=O)[CH:5]=[CH:6][CH:7]=1.C.O.NN>CO>[NH2:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]#[N:14]
Reactant: N#Cc1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1ccc(Nc2cccc(Br)c2)c(N)c1
Temperature: 80 °C

Procedure:
To a solution of compound C (1 g, 3.14 mmol) in methanol (10 mL) was added anhydrous FeCl3 (100 mg, 0.65 mmol) and charcoal (100 mg). The mixture was stirred at 60° C. and at that temperature hydrazine hydrate (10 mL) was added slowly where after the temperature was raised to 80° C. for 1.5 h. The reaction mixture was cooled to RT, filtered through a small pad of celite and washed with methanol. The organic layer was concentrated and washed with water, to give light brown solid D (200 mg, 22%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Nc1ccc(Sc2ccccn2)c(Cl)c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 642.1 mg (2.81 mmol) of 3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 4-[3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile as a yellow solid, mp 225-228° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=O)=[N:6][N:5]=[CH:4][NH:3]1.[NH3:13]>C(O)C>[O:1]=[C:2]1[C:7]([C:8]([NH2:13])=[O:10])=[N:6][N:5]=[CH:4][NH:3]1
Reactant: N
Reactant: CCOC(=O)c1nnc[nH]c1=O
Solvent: CCO
Product: NC(=O)c1nnc[nH]c1=O
Reaction time: 0.33 h

Procedure:
In 5 mL of ethanol is dissolved 0.06 g of ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylate. At 10° C., the solution is saturated with ammonia by introducing gaseous ammonia thereinto for 20 minutes. The solution is allowed to stand at ambient temperature for 15 hours, and the resulting crystals are collected by filtration. The crystals thus obtained are washed successively with two 2 mL portions of ethanol and then two 1 mL portion of methanol to obtain 0.03 g of 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxamide.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:33])[CH:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:17]([NH:16][C@@H:13]2[C@@H:11]3[C@@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)=[O:33])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
N-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2,2-bis(4-fluorophenyl)acetamide (150 mg, 0.336 mmol) from Example 228 and ethanol (20 mL) were added to 20% Pd(OH)2 on carbon, wet (30.0 mg, 0.214 mmol) in a 50 mL pressure bottle and stirred for 2 hours under 30 psi hydrogen at 50° C. The mixture was filtered and the solvent was removed in vacuo to give 2,2-bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.09 (d, J=7.1, 1H), 7.60-7.55 (m, 4H), 7.13 (q, J=8.2, 4H), 5.26 (s, 1H), 4.36-4.27 (m, 1H), 3.06 (dd, J=10.9, 2.7, 1H), 2.92 (dd, J=10.9, 7.0, 1H), 2.81 (dd, J=10.7, 7.0, 1H), 2.59 (dd, J=10.8, 2.8, 1H), 2.52-2.41 (m, 2H), 2.33-2.25 (m, 1H), 2.06-1.96 (m, 1H), 1.83 (td, J=12.7, 6.9, 1H), 1.65-1.52 (m, 1H), 1.26 (ddt, J=12.3, 8.7, 6.1, 1H); MS (ESI+) m/z 357 (M+H)+.
Reaction SMILES: C([C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][OH:18])#C.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[CH2:28](N(CC)CC)[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:18][CH:17]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[C:12]=2[CH:3]=1)[C:28]#[C:29][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#Cc1c(CO)ccc2c1C(C)(C)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 1 h

Procedure:
2.42 g (10 mmol) of -ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, 2 g (11 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 169 mg (0.75 mmol) of palladium(II) acetate and 393 mg (1.5 mmol) of triphenylphosphine were successively added. Heating was carried out at 60° C. for one hour, the reaction mixture was evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). 1.23 g (35.5%) of 4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzaldehyde, with a melting point of 104°-105° C., was recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][OH:19])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:33][CH2:34][C:35]([O-:37])=[O:36].[Na+]>C(O)(C)(C)C>[ClH:33].[ClH:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][CH2:34][C:35]([OH:37])=[O:36])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: OC/C=C/CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C([O-])CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cl
Product: O=C(O)COC/C=C/CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
To a stirred solution of 4-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-yl}-(E)-but-2-en-1-ol (247.0 g, 0.689 mol) and potassium tert-butoxide (139.2 g, 1.240 mol) in anhydrous tert-butanol (2000 ml), preheated at 60-65° C. for 1 hr. under nitrogen atmosphere, is added dry sodium chloroacetate (160.5 g, 1.378 mol). The reaction mass is then refluxed for further 5 hrs. The mixture is then concentrated under reduced pressure at below 60° C. until tert-butanol is completely removed. The residue is taken up in water (1500 ml) and washed with ethyl acetate (2×1500 ml). The aqueous solution is then acidified to pH 5-6, extracted into dichloromethane (2×750 ml), washed dichloromethane layer with water (300 ml), and concentrated to get crude product as a foamy solid. The crude product is purified by flash column chromatography on silica gel using toluene-methanol (4:1) as mobile phase. The product was converted to its dihydrochloride salt as in example 17.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7].[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].C[Si]([C:36]#[N:37])(C)C.N>C(O)(=O)C>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([Cl:24])[CH:26]=2)([C:36]#[N:37])[CH2:10][CH2:9]1)=[O:7]
Reactant: C[Si](C)(C)C#N
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: N
Solvent: CC(=O)O
Product: N#CC1(Nc2cccc(Cl)c2)CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.3 %

Procedure:
To a solution of 1-(3,5-bis-trifluoromethyl-benzoyl)-piperidin-4-one (5.1 g, 15 mmol) in acetic acid (20 mL) were added with cooling 3-chloroaniline (1.7 mL, 16.5 mmol) and trimethylsilylcyanide (1.9 mL, 15 mmol) so that the temperature did not rise above 20° C. The suspension was stirred for 6 h at room temperature. The reaction mixture was than added to ice-water (350 mL), ammonia (55 mL, 25%) was added to the mixture which was stirred for 15 min. After that the mixture was extracted with dichloromethane, the organic phases were pooled, washed with brine and dried with MgSO4. The solvent was evaporated and the residue crystallized from ethylacetate to yield the desired product (5.3 g, 74%), m.p. 205-207° C. and MS: m/e=476.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([CH2:17][OH:18])([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])[CH2:4][O:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])([CH2:17][O:18][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][O:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1
Product: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1

Procedure:
The obtained 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane is reacted with p-toluenesulfonyl chloride by for example a method of L. F. Fieser et al. (Reagents for Organic Synthesis, Vol. 1, Wiley, New York, p. 1179 (1967)) and purified, to give the desired 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane (FIG. 1, Step 5).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([C@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:10]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1[C@@H]1CCc2ccccc21

Procedure:
According to the method of Example 168, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with (R)-(−)-aminoindane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C1C(=O)N([O:17][C:18]([CH2:20][I:21])=O)C(=O)C1.C(N(CC)C(C)C)(C)C>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:18](=[O:17])[CH2:20][I:21])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: O=C(CI)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CNC(=O)CI)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
FIG. 11 illustrates the synthesis of Mass Tag (2). 4-Amino-benzylamine (Aldrich, 1 mmol), N-succinimidyl iodoacetate (Pierce, 1 mmol), and N,N-diisopropyl ethylamine (DIEA, 100 μL) were mixed in dichloromethane (10 mL) and stirred at room temperature for 1 hr. Solvent was removed under reduced pressure. The product was purified by silica gel column chromatography, eluting with hexane, ethyl acetate (20%-60%), to give 4-amino-N-iodoacetylbenzylamine (62.2% yield). 1H NMR (MeOD): 7.1 (d, 2H), 6.75 (d, 2H), 4.21 (s, 2H), 3.65 (s, 2H). [M+H]+ in MS: 291.0, calculated; 291.0, found.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([O:13][C:14]([CH3:17])(C)C)=[O:12])[NH:2]1.[C:18]([S:26][CH2:27][CH:28]([CH3:32])[C:29]([OH:31])=O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ON1[C:38]2C=CC=C[C:37]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:18]([S:26][CH2:27][CH:28]([CH3:32])[C:29]([N:2]1[C@H:3]([C:11]([O:13][CH2:14][CH2:17][CH2:37][CH3:38])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:31])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)[C@@H]1Cc2ccccc2CN1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@@H]1Cc2ccccc2CN1C(=O)C(C)CSC(=O)c1ccccc1
Reaction time: 3 h
Yield: 73.7 %

Procedure:
3.73 g of tert.-butyl (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, 3.58 g of 3-benzoylthio-2-methylpropionic acid and 2.16 g of 1-hydroxybenzotriazole are dissolved in 60 ml of tetrahydrofuran, and a solution of 3.3 g of dicyclohexylcarbodiimide in 10 ml of tetrahydrofuran is added dropwise thereto at -15° C. After said dropwise addition, the mixture is stirred at a temperature below -10° C. for 3 hours and then at room temperature overnight. Insoluble materials are removed by filtration. The filtrate is distilled under reduced pressure to remove solvent. Water is added to the residue obtained, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous 3 % citric acid solution, water, an aqueous sodium bicarbonate solution and water, sucessively. Then, the extract is dried and distilled to remove solvent. The residue thus obtained is purified by silica gel column chromatography. 5.18 g of ter.-butyl (3S)-2-(3-benzoylthio-2-methylpropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate are thereby obtained as colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[OH-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)cc2cccnc12
Yield: 32.3 %

Procedure:
A solution of 6-methoxy-8-nitro-quinoline (9 g, 44.1 mmol) in HBr (100 mL) was heated at 110° C. overnight. Additional HBr (80 mL) was added and the reaction continued to heat for an additional 24 hours. The cooled reaction mixture was basified with 2.5 N NaOH (800 mL) and extracted into EtOAc (2×300 mL). The organic fractions were combined, dried over Na2SO4 and purified by column chromatography (50% EtOAc/hexane) to afford 2.71 g (32%) of the title compound as a white solid: mp discolors above 100° C., MS (−) ESI m/z 189 [M−H]−.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:9]=1[C:43]([O:45]CC)=[CH2:44].C(O)(C(F)(F)F)=O>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][CH:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)[C:9]=1[C:43](=[O:45])[CH3:44]
Reactant: C=C(OCC)c1c(OC2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1c(OC2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reaction time: 8 h

Procedure:
The crude tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate was treated with 50% TFA in H2O (6 mL) and stirred overnight. The reaction mixture was concentrated in vacuo. Purification with prep-LC provided 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone: LCMS tR=1.11 Min (5 min run, UV254nm). Mass calculated for, M+ 428.1, observed LC/MS m/z 429.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@H:20]([CH3:24])[CH2:21][NH:22][CH3:23])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25].[C:26]([OH:30])(=O)[CH2:27][OH:28].OCC(N(CCOC1C=CC=C2C=1C(NC1C=CC(O)=C(C)C=1)=NC=N2)C)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:25])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][C@H:20]([CH3:24])[CH2:21][N:22]([CH3:23])[C:26](=[O:30])[CH2:27][OH:28])[N:12]=[CH:11][N:10]=1
Reactant: O=C(O)CO
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Product: C[C@H](CN(C)C(=O)CO)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12

Procedure:
The N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-2-hydroxy-N-methylacetamide starting material was prepared by reacting 2-chloro-4-({5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol with and glycolic acid using an analogous procedure to that described in Example 3 for the preparation of 2-hydroxy-N-[2-({4-[4-hydroxy-3-methylanilino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide, to give N-[(2R)-2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)propyl]-2-hydroxy-N-methylacetamide in 57% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.91 (m, 1H), 2.97 (s, 3H), 3.39 (dd, 1H), 4.04 (d, 2H), 4.16 (m, 1H), 4.39 (m, 1H), 5.08 (m, 1H), 6.98 (d, 1H), 7.27 (m, 2H), 7.47 (dd, 1H), 7.70 (t, 1H), 7.97 (d, 1H), 8.43 (s, 1H), 9.85 (s, 1H), 9.99 (bs, 1H); Mass spectrum MH+ 417.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:17])(=[O:16])[CH2:12]C(O)=O.C([O-])(=O)C.[NH4+:22]>C(O)C>[NH2:22][CH:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[F:1])[CH2:12][C:11]([OH:17])=[O:16]
Reactant: O=Cc1cc(F)ccc1F
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cc(F)ccc1F
Reaction time: 8 h

Procedure:
A solution of 2,5-difluorobenzaldehyde (5 g), malonic acid (3.66 g) and ammonium acetate (5.42 g) in ethanol (50 ml) was heated under reflux for six hours. The mixture was cooled and left to stand overnight. The crystals formed were filtered off and washed with ethanol (5 ml).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6]Cl.Cl.[Cl:13][C:14]1[CH:15]=[N:16][C:17](=[O:20])[NH:18][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][N:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][C:17]1=[O:20]
Reactant: Cc1ccccc1COCCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1COCn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of chloromethyl 2-methylbenzyl ether (see Preparation 3a and 3b) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred for 2 hours at room temperature. It was then washed with water and the dried (MgSO4) solution evaporated to yield a crude mixture (2.55 g, 96%) which was purified by trituration with ether. The yield of the title compound was 1.33 g (50%), m.p. 88° C. 1H NMR (CDCl3): δ2.26 (Me), 4.63 (CH2 -Ph), 5.30 (CH2O), 7.00 (Ph), 7.60 and 8.37 (H-4, H-6, J 4 Hz). IR(KBr): 1660 cm-1 (CO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16]([S:28][CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=[O:40])CCC1=O>ClCCCl.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:23])([F:25])[F:24])=[O:19])=[C:16]([S:28]([CH3:29])=[O:40])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCCl
Product: CS(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 43.4 %

Procedure:
In a solution of 0.38 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylthio-N-(2,2,2-trifluoroethyl) benzoic acid amide (Compound of the present invention No. 5-322) synthesized similarly to Synthetic Example 13 in 6 ml of 1,2-dichloroethane, 0.10 g of N-chlorosuccinic acid imide was added with stirring at room temperature, and stirred at the same temperature for 11 hours. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of saturated sodium hydrogen carbonate, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2), and 0.17 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1.O>C(#N)C>[CH:1]([NH:4][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 30.3 %

Procedure:
430 μl (5 mmol) of isopropylamine and 420 mg (3 mmol) of potassium carbonate are added to a solution of 600 mg (1 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetonitrile. The reaction mixture is stirred at reflux overnight. The reaction is stopped by adding water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (50/50 heptane/ethyl acetate). 160 mg of ethyl 4′-(3-isopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellowish solid (m.p.=171° C., yield=30%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:42][O-].[Na+]>C(Cl)Cl.CO>[CH2:29]([N:27]([CH3:28])[C:25]1[C:24]([C:33]([F:35])([F:36])[F:34])=[CH:23][C:18]2[NH:19][C:20](=[O:22])[CH2:21][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][O:1][CH3:42])[CH:8]=4)[CH:10]=3)=[N:16][C:17]=2[CH:26]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: C[O-]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 366) (248 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of Example 288. Obtained as a light yellow solid (58 mg, 23%).