Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH:27][C:28]3[N:37]=[CH:36][C:35]4[N:34]([CH3:38])[C:33](=[O:39])[C@@H:32]([CH2:40][CH3:41])[N:31]([CH:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[C:30]=4[N:29]=3)=[C:22]3[O:26][CH2:25][CH2:24][C:23]=23)=[O:17])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:42]1([N:31]2[C:30]3[N:29]=[C:28]([NH:27][C:21]4[CH:20]=[CH:19][C:18]([C:16]([NH:15][CH2:14][CH:10]5[O:11][CH2:12][CH2:13][NH:8][CH2:9]5)=[O:17])=[C:23]5[C:22]=4[O:26][CH2:25][CH2:24]5)[N:37]=[CH:36][C:35]=3[N:34]([CH3:38])[C:33](=[O:39])[C@H:32]2[CH2:40][CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CN(Cc5ccccc5)CCO4)c4c3OCC4)nc2N1C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CNCCO4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 101.4 %

Procedure:
N-[(4-benzylmorpholin-2-yl)methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 2e (0.19 g, 0.30 mmol) was dissolved in 30 mL of methanol followed by the addition of palladium/carbon (40 mg, 10%), filled with hydrogen two times. The reaction solution was stirred for 2 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(morpholin-2-ylmethyl)-2,3-dihydrobenzofuran-4-carboxamide 2f (163 mg) as a white solid, which was used in the next step without further furification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([OH:27])[CH:3]=1.[CH2:28]([N:30](CC)CC)C.N#CBr>C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([O:27][C:28]#[N:30])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1O
Agent: N#CBr
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1OC#N
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.168 g, 0.427 mmol) in methylene chloride (2 mL) was added triethylamine (0.12 mL, 0.86 mmol). The solution was cooled to −5° C. via an acetone/ice bath then cyanogen bromide was added (0.22 mL, 0.66 mmol). The reaction was stirred at −5° C. for 30 minutes then concentrated in vacuo to give the crude title compound which was taken directly on to the next step (0.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14](=[CH2:18])[CH2:15][CH2:16]O)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([I:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[N-:44]=[N+:45]=[N-:46].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14](=[CH2:18])[CH2:15][CH2:16][N:44]=[N+:45]=[N-:46])[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([I:19])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(CCO)CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(CCN=[N+]=[N-])CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of N-(4-Chloro-2-iodo-phenyl)-N-(4-hydroxy-2-methylene-butyl)-methanesulfonamide obtained in Step A and triphenylphosphine (3.5 g) in dimethylacetamide (80 ml) at −10° C. under argon was added carbon tetrabromide (4.5 g). The reaction mixture was stirred at −10° C. for 45 min (a precipitate formed). Sodium azide (2 g) was added in one portion and the reaction mixture was stirred at 45° C. for 1 hour, cooled to room temperature, poured into water, extracted with ethyl acetate; the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 7:3) to afford N-(4-Chloro-2-iodo-phenyl)-N-(4-azido-2-methylene-butyl)-methanesulfonamide (1.96 g). 1H NMR (CDCl3, 400 MHz) 2.50 (m, 2H), 3.48 (m, 2H), 4.19 (d, J=12.0 Hz, 1H), 4.40 (d, J=12.0 Hz, 1H), 4.90 (s, 1H), 5.01 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.36 (dd, J=0.9H, 8.5 Hz, 1H), 7.92 (d, J=0.9 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28](OCC)=[O:29].[CH3:33][NH:34][NH2:35]>O1CCOCC1>[CH3:33][N:34]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:7](=[O:19])[NH:6][C@H:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:4]=2[C:28](=[O:29])[NH:35]1
Reactant: CNN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Solvent: C1COCCO1
Product: CN1CC2=C(C(=O)N1)[C@@H](c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
101 g (198.7 mmol) of ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 6A) were initially charged in 2400 ml of dioxane. 27.46 g (596.1 mmol) of methylhydrazine were added dropwise to the solution, and the reaction mixture was then stirred at boiling point for 3 h. The mixture was then concentrated, and the residue was dissolved in dichloromethane and washed with water. The organic phase was dried over sodium sulphate and concentrated. The residue that remained was chomatographed on silica gel (mobile phase: dichloromethane/methanol 95:5). The solid which was obtained after concentration of the product fractions was triturated with diethyl ether, filtered off with suction and then dried at 50° C. under reduced pressure for 4 days. This gave 56.8 g (66% of theory) of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Reactant: Nc1ccccc1Cl
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(3-methylthiopropoxy)quinoline (0.95 g, 2.8 mmol) and 2-chloroaniline (1.51 g, 11.8 mmol) in toluene was heated to 55° C. and stirred overnight. The solvent was evaporated and the residue was partioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 0.95 g (74%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[N:19]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:27][C:23]1[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=1)[N:18]([CH2:17][C:16]1[CH:28]=[CH:29][CH:30]=[C:14]([F:13])[CH:15]=1)[N:19]=[CH:20]3)=[N:3][CH:4]=[N:5]2
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: Fc1cccc2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cccc(F)c45)ccc32)c1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
A mixture of 4-chloro-5-fluoroquinazoline (1.82 g, 10 mmol), 1-(3-fluorobenzyl)-1H-indazol-5-amine (2.41 g, 10 mmol, obtained as described in WO 98/02438) and diisopropylethylamine (1.74 ml, 10 mmol) in isopropanol (20 ml) was heated at 80° C. for 45 minutes. On cooling to ambient temperature, the product was filtered off and washed with isopropanol and ether. The precipitated solid was dried under high vacuum to give 5-fluoro-N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]quinazolin-4-amine (3.2 g, 83%); NMR Spectrum (CDCl3) 5.61 (s, 2H), 6.88 (d, 1H), 6.98 (m, 2H), 7.25 (m, 2H), 7.37 (d, 1H), 7.53 (dd, 1H), 7.73 (m, 2H), 8.09 (s, 1H), 8.19 (s, 1H), 8.49 (d, 1H), 8.69 (s, 1H); Mass spectrum MH+ 388.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:35][CH2:36]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3C)c2cc1C#N
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (2.0 ml) and diethylamine (0.50 ml) to N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxyquinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea (80 mg), the mixture was heated at 60° C. for 6 hours. The reaction solution was allowed to cool, and the precipitated crystals were filtered out to obtain the title compound (32 mg) as light brown crystals.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>ClCCl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:6]2)[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.040 mmol, racemic intermediate from Example 139, Step 6) and triethylamine (20 μL, 0.14 mmol) in dichloromethane (0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.048 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated under reduced pressure and the crude mixture purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.8 mg, 19%). The product was isolated as a racemic mixture. LCMS calculated for C21H24ClF4N6O (M+H)+: m/z=487.2; Found: 487.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[F:41][C:42]([F:71])([F:70])[CH2:43][O:44][C:45]1[CH:46]=[CH:47][C:48]([C@H:51]([NH:53][C:54]([C@H:56]2[CH2:58][C@@H:57]2[C:59]2[CH:69]=[CH:68][C:62]([O:63][CH2:64][C:65](O)=[O:66])=[CH:61][CH:60]=2)=[O:55])[CH3:52])=[N:49][CH:50]=1.Cl>>[F:33][C:34]1([F:40])[CH2:39][CH2:38][N:37]([C:65](=[O:66])[CH2:64][O:63][C:62]2[CH:61]=[CH:60][C:59]([C@H:57]3[CH2:58][C@@H:56]3[C:54]([NH:53][C@@H:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH2:43][C:42]([F:41])([F:70])[F:71])=[CH:50][N:49]=3)[CH3:52])=[O:55])=[CH:69][CH:68]=2)[CH2:36][CH2:35]1
Reactant: FC1(F)CCNCC1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)N2CCC(F)(F)CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture of HBTU (28 mg, 0.075 mmol), triethylamine (0.03 mL, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) and 2-(4-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetic acid (28 mg, 0.050 mmol) was stirring for 4 hours at room temperature. The mixture was poured into 2 mol/l hydrochloric acid, and the aqueous layer was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 13.7 mg (50% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[NH:7][C:8]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH:12]([C:8]1[NH:7][C:6](=[O:18])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: BrBr
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide and sodium acetate (930 mg, 3 eq.) in acetic acid (15 ml), was added bromine (190 ul, 1 eq.). The reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (0.95 g) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.CO[C:22]1[CH:23]=[C:24]([CH:26]=[C:27](OC)[C:28]=1OC)[NH2:25].CCOC(C)=O>C(O)(C)C>[C:24]1([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=[CH:22][CH:23]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(c1cccnc1)N1CCc2nc(Nc3ccccc3)ncc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4,5-trimethoxyaniline (0.021 g, 0.0498 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 54.8% yield (0.021 g, 0.049 mmol).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=O)[CH3:18])[CH:9]=1.Cl.[NH2:31][OH:32]>CCO.N1C=CC=CC=1>[CH3:29][Si:2]([CH3:28])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=[N:31][OH:32])[CH3:18])[CH:9]=1
Reactant: NO
Reactant: CC(=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.1 %

Procedure:
A solution of 1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)pyrazolo[1,5-a]pyrimidin-5-yl]ethanone (4.34 g, 9.94 mmol) in 1:1 EtOH/pyridine (50 mL) was treated with hydroxylamine hydrochloride (3.45 g, 49.7 mmol). The resulting mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to remove most solvent. The residue was partitioned between EtOAc (100 mL) and water (60 mL), the layers were separated, and the organic phase was washed with water (60 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound, 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethanone oxime (4.90 g, 85% purity, 93% yield) as an off-white semisolid: MS (ESI+) for C20H37N5O3Si2 m/z 452 (M+H)+.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:11]=[CH:12][CH:13]=O.[C:19]([CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[O:23])#[N:20]>C(O)C>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:22](/[C:21](=[CH:13]/[CH:12]=[CH:11]/[C:10]1[CH:15]=[CH:16][C:17]([OH:18])=[C:8]([OH:7])[CH:9]=1)/[C:19]#[N:20])=[O:23]
Reactant: N#CCC(=O)NCc1cccc(F)c1
Reactant: O=CC=Cc1ccc(O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#C/C(=C\C=C\c1ccc(O)c(O)c1)C(=O)NCc1cccc(F)c1

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 3,4-dihydroxycinnamaldehyde (35 mg, 0.2 mmol) and 2-cyano-N-(3-fluorobenzyl)acetamide (38 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (51 mg, 75%). The product gave the following analytical data:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:20])=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(F)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N(CCCCCCCC(=O)O)C(=O)c2ccc(F)cc2)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 7.4 g (18 mmol) of 8-[4-fluoro-N-(4-methoxyphenyl)-benzamido]-caprylic acid methyl ester, 1.4 g (35 mmol) of sodium hydroxide and 70 cc. of methanol. Reaction time: 10 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[N:8]([CH3:16])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.O>CS(C)=O.ClCCl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]3)=[CH:35][CH:36]=2)=[O:17])[N:8]([CH3:16])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Nitrogen gas is bubbled through a solution of (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (1.65 g, 5.01 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 5.02 mmol) in DMSO (20 mL) for 2 min. Next, N,N-diisopropylethylamine (2 mL, 11.48 mmol) is added. The reaction mixture is stirred at 60° C. for 6 hours. Then, the reaction mixture is distributed between water (150 mL) and dichloromethane (100 mL). The aqueous layer is isolated and extracted with dichloromethane (2×100 mL). The combined organic phases are washed with water (100 mL) and aqueous sodium chloride (100 mL), and dried over anhydrous sodium sulfate. After removal of solvent, the crude product is purified on a silica gel chromatography with ethyl acetate-hexanes (25%) to give a white solid (2.28 g, 97%, ES−(m/z) 470.1 [M−H]).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH2:6][CH2:5][C:1]#[N:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#CCCC=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of 73.g (1.5 mol) of sodium cyanide in 1 liter of hexamethylphosphoramide at ambient temperature was added over a 1 hour period a solution of 290. g (1 mol) of 4-bromo-1,1-diphenyl-1-butene in 0.5 liters of hexamethylphosphoramide. The mixture was stirred overnight, poured into 2 liters of water and extracted with 3×1 liters of ether. The ether extracts were combined, washed with 3×0.5 liters of Water, 0.5 liters of brine, and dried over sodium sulfate. The resulting crude solid was recrystallized from isopropyl ether to give 190 .g (80%) of 5,5-diphenyl-4-pentenenitrile as a white solid (mp 64°-66° C.) .
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[C:3]([F:11])([F:10])[C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[H-].[Na+].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.O>CN(C)C=O>[Cl:26][C:25]1[C:20]([N:7]2[C:8]([CH3:9])=[C:4]([C:3]([F:11])([F:10])[C:2]([F:1])([F:16])[C:12]([F:14])([F:15])[F:13])[N:5]=[CH:6]2)=[N:21][CH:22]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:24]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)C(F)(F)C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
To a solution of 0.6 g (2.4 m mol) of 4-heptafluoropropyl-5-methylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 100 mg (2.4 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.52 g (2.4 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product was subjected to silica gel chromatography to give 0.4 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-heptafluoropropyl-5-methylimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:34]([CH3:36])[CH3:35])[CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:20][CH:19]=1.[ClH:37]>CCOCC>[ClH:37].[NH2:26][CH2:25][CH:24]([C:21]1[CH:20]=[CH:19][C:18]([C:4]2[C:5]3[C:6]4[CH:17]=[CH:16][S:15][C:7]=4[C:8](=[O:14])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[O:2][CH3:1])=[CH:23][CH:22]=1)[CH:34]([CH3:35])[CH3:36]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN)C(C)C)cc1
Yield: 92 %

Procedure:
Following General Procedure D1, tert-butyl 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)-3-methylbutylcarbamate (50 mg, 0.060 mmol) was reacted with HCl in ether (3 mL) to afford the desired product (37 mg, 92%) as an off-white solid: ESI MS m/1407 [C24H26N2O2S+H]+.