Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][N:16]1[CH2:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18](=[O:32])[CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]([CH3:12])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[N:26][C:20]4[NH:19][C:18](=[O:32])[CH2:17][N:16]([CH3:15])[CH2:22][C:21]=4[CH:23]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3ccc4[nH]ccc4c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of (1H-indol-5-ylmethyl)methylamine (143 mg, 0.9 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (250 mg, 0.8 mmol), HOBt (121 mg, 0.9 mmol) and diisopropylethylamine (0.61 mL, 3.6 mmol) in DMF (25 mL) was added EDC hydrochloride (172 mg, 0.9 mmol). The mixture was stirred overnight at room temperature. Water (100 mL) was added and the solution was stirred for 1 hr. The precipitate was collected by filtration. The yellow solid was preabsorded onto silica gel and purified by column chromatography (95:5 CH2Cl2/MeOH) to afford (E)-N-(1H-indol-5-ylmethyl)-N-methyl-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (195 mg, 63%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 11.07 (d, J=7.6 Hz, 1H), 10.37 (m, 1H), 8.52 (dd, J=7.0, 1.9 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.59-7.26 (m, 5H), 7.07-6.92 (m, 1H), 6.38 (d, J=1.9 Hz, 1H), 4.66-4.85 (2×s, 2H), 3.74-3.77 (m, 2H), 3.42-3.38 (m, 2H), 3.08-2.90 (2×s, 3H), 2.37-2.32 (2×s, 3H); ESI MS m/z 390 [C22H23N5O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=2[Cl:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br.CO.O>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(Oc2ccc(C#N)c(Cl)c2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Oc2ccc(O)cc2Cl)cc1Cl

Procedure:
0.5 g (1.7 mmol) of 2-chloro-4-(2-chloro-4-methoxy-phenoxy)-benzonitrile and 2.21 mL (2.21 mmol) of boron tribromide 1M in dichloromethane were stirred in 5.5 mL dichloromethane for 5 days at RT. The mixture was carefully combined with methanol and then water and dichloromethane were added. The phases were separated and the aqueous phase was extracted twice more with dichloromethane. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: NC1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1>[CH3:15][CH2:11][O:10][C:8]([CH3:6])=[O:9].[CH3:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(N)cc(B(O)O)c1
Agent: Cc1ccccc1CCO
Agent: [K+]
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-5-methoxycarbonylphenylboronic acid (161 mg, 0.82 mmol), Pd(0) [PPh3]4 (50 mg, 5 mol %), potassium carbonate (905 mg, 6.6 mmol) and 2-(2-benzyloxy-5-chloro)phenyl-1-bromocyclopent-1-ene (298 mg, 0.82 mmol) in toluene-ethanol (1:1 10 mL) were stirred at 90° C., under nitrogen, for 2 hrs. After cooling the reaction mixture was poured onto water (10 ml) and extracted with diethyl ether (2×10 ml). The combined extracts were dried and evaporated. Flash chromatography [EtOAc/Iso-hexane 5:95-1:4] gave the product as a yellow oil 200 mg 56% LC/MS: Rt=4.00 [M+H] 434 (1 Cl)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15](=[O:17])[CH3:16].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=2)[CH:11]=[CH:10][C:9]=1[C:15](=[O:17])[CH3:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Potassium carbonate (2.5 eq) was added to a solution of 2′,4′-dihydroxyacetophenone (1 eq) in acetonitrile (400 mL), and the suspension stirred at room temperature. Benzyl bromide (2.5 eq) was added drop wise over 10 minutes and the mixture heated at reflux for 18 hours. The mixture was cooled and evaporated in vacuo to give slurry. The slurry was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with dichloromethane and the organic extracts were combined, dried (MgSO4) and evaporated in vacuo. The product was triturated with hexane, filtered and washed with cold hexane and dried in vacuo at 45° C. to give 1-(2,4-Bis-benzyloxy-phenyl)-ethanone as a white powder.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[S:22](=[O:24])(=[O:23])[N:21](C(OC)=O)[CH2:20][CH2:19][CH:18]3[CH3:29])=[C:12]([F:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH:18]([CH3:29])[CH2:19][CH2:20][NH:21][S:22]3(=[O:24])=[O:23])=[C:12]([F:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)N1CCC(C)N(Cc2ccc(N3CCN(C(C)=O)CC3)cc2F)S1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(CN3C(C)CCNS3(=O)=O)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of methyl 6-{[4-(4-acetylpiperazin-1-yl)-2-fluorophenyl]methyl}-5-methyl-1,1- dioxo-1λ6,2,6-thiadiazinane-2-carboxylate (420 mg, 0.95 mmol) and NaOH (76 mg, 1.90 mmol) in MeOH/H2O (1:1, 10 mL) was stirred at 0° C. for 10 minutes and ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (1% (NH4)2CO3) to afford 2-{[4-(4-acetylpiperazin-1-yl)-2-fluorophenyl]methyl}-3-methyl-1λ6,2,6-thiadiazinane-1,1-dione as white solid (300 mg, 82%). 1H NMR (500 MHz, CDCl3) δ 7.42 (t, 1H), 6.68 (dd, 1H), 6.54 (dd, 1H), 4.373 (d, 1H), 4.22 (d, 1H), 3.85-3.90 (m, 1H), 3.76 (t, 2H), 3.61 (t, 2H), 3.53 (dd, 2H), 3.14-3.20 (m, 4H), 2.14 (s, 3H), 1.58-1.67 (m, 2H), 1.23 (d, 3H).
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=1)=[O:23]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=1)=[O:23]
Reactant: O=C(CBr)c1cccc(OC(F)F)c1
Reactant: N#CN
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4cccc(OC(F)F)c4)s3)cc2)CC1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1) and 2-bromo-1-(3-difluoro-methoxyphenyl)ethanone (of Example 14L) following the procedure used in Example 24. Mass spectrum (ES) MH+=460.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=O.C1(P(=[CH:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:41]([O:40][C:38](/[CH:37]=[CH:1]/[C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: COC(=O)c1cccc(-n2cccc2C=O)c1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-n2cccc2/C=C/C(=O)OCc2ccccc2)c1
Yield: 48.8 %

Procedure:
The solution of methyl 3-(2-formylpyrrol-1-yl)benzoate (1.0 g) and benzyl (triphenylphosphoranylidene)acetate (1.8 g) in tetrahydrofuran (10 ml) were heated under reflux for 30 hours. After evaporating the solvent, the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-[2-((E)-2-benzyloxycarbonylethenyl)pyrrol-1-yl)benzoate (0.77 g) as an oil.
Reaction SMILES: [CH3:1][Li].[OH:3][CH:4]1[CH:9]2[C:10]([CH3:16])([CH3:15])[CH:11]3[CH2:14][C:8]2([CH2:13][CH2:12]3)[C:7]([CH3:18])([CH3:17])[CH2:6][C:5]1=[O:19].[Cl-].[NH4+]>C(OCC)C>[CH3:17][C:7]1([CH3:18])[CH2:6][C:5]([CH3:1])([OH:19])[CH:4]([OH:3])[CH:9]2[C:10]([CH3:15])([CH3:16])[CH:11]3[CH2:14][C:8]12[CH2:13][CH2:12]3
Reactant: [Li]C
Reactant: CC1(C)C2CCC3(C2)C1C(O)C(=O)CC3(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CC(C)(C)C23CCC(C2)C(C)(C)C3C1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
Methyllithium (63 ml of a 1.6M solution in diethyl ether, 0.10 mol) was added over 1 h to a solution of crude 5-hydroxy-2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undecan-4-one (4, 20 g, obtained as in Example 1c) in diethyl ether (200 ml), cooled below 10° C. After 1.5 h stirring, an additional portion of methyllithium (50 ml of a 1.6M solution in diethyl ether, 0.080 mol) was added and stirring continued overnight at room temperature. The reaction mixture was poured onto a stirred mixture of saturated aqueous solution of ammonium chloride (200 ml) and ice (100 g), the phases separated and the aqueous phase extracted with MTBE (200 ml). The combined organic phases were washed with water (3×200 ml), dried (Na2SO4), concentrated in vacuo and the residue (21 g) purified by flash chromatography (MTBE/hexane 1:3 to 1:2) to afford 2,2,4,7,7-pentamethyltricyclo[6.2.1.01.6]undecane-4,5-diol (5b, 5.7 g, ˜46% yield starting from 3, white solid).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][P:9]([N:14]1[CH:20]2[CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:19]2)([O:11][CH2:12][CH3:13])=[O:10])[CH3:7].O>C1COCC1>[CH:1]1([C@@H:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][C@H:20]2[NH:14][P:9]([O:8][CH2:6][CH3:7])([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: Br[Mg]C1CC1
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CC1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a suspension of Cu(I)I (0.15 g, 0.77 mmol) in THF (20 mL) was slowly added 0.50M cyclopropylmagnesium bromide (61.2 mL, 30.6 mmol) in THF at −30° C. After stirring at that temperature for 15 minutes, a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (2.82 g, 7.66 mmol; Example H, Step D) in THF (10 mL) was added at −30° C., and then the mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. Water (50 mL) was added and extracted with ethyl acetate (2×40 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 4-cyclopropyl-3-(diethoxyphosphorylamino)piperidine-1-carboxylate (1.84 g, 59%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]([S:26][CH3:27])[N:15]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](/[CH:25]=[CH:32]/[N:33]([CH3:35])[CH3:34])[N:17]=[C:16]([S:26][CH3:27])[N:15]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in Example 1e by starting from ethyl 4-(3,5-bis(trifluoro methyl)phenylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.52 g, 3.6 mmol) and N,N-dimethylformamide dimethylacetal (743 uL, 5.2 mmol) and continuing until the reaction yielded the crude title compound (E)-ethyl 4-(3,5-bis(trifluoromethyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-(methyl thio)pyrimidine-5-carboxylate. The resultant compound was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:24])[CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:23]=[N:22]2
Reactant: C#CCCc1cnc2cc(F)ccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cnc3cc(F)ccc3n2)n1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (43 mg, 0.22 mmol) and 2-but-3-ynyl-6-fluoro-quinoxaline (45 mg, 0.22 mmol). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 45 mg (0.15 mmol, 65%) of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as an orange solid with a purity of 85%.
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[C:5]([NH:20][CH:21]([C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:22][C:23]([O:25]CC)=[O:24])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[NH:12][CH:11]=2)=[N:8][CH:9]=1>O.C1COCC1>[F:3][C:4]1[C:5]([NH:20][CH:21]([C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:22][C:23]([OH:25])=[O:24])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[NH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1(C)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)CCCCC1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
LiOH (0.118 mg, 4.927 mmol) was added to a solution of ethyl 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)-propanoate, 77, (0.23 g, 0.49 mmol) in water (5 mL) and THF (5 mL). The solution was stirred at 95° C. for 18 hours and then cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and neutralized with 2N HCl. The resulting precipitate was extracted with EtOAc (3×10 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford 210 mg of the desired product as an off-white solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (dd, J=9.7, 2.7 Hz, 1H), 8.16 (s, 2H), 7.99 (d, J=4.1 Hz, 1H), 5.20 (d, J=9.9 Hz, 1H), 2.86-2.69 (m, 1H), 2.53 (dd, J=14.7, 11.0 Hz, 1H), 1.76-1.56 (m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.20 minutes (M+H) 416.27.
Reaction SMILES: C([N:3]([C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:19]([C:20](=O)[CH3:21])=[C:18]([CH3:23])[N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:16](=[O:34])[N:15]1[CH3:35])[NH2:4])=O.[OH-:37].[CH3:38]OC(NS([N+](CC)(CC)CC)(=O)=O)=O>ClCCl>[C:20]([C:19]1[CH:14]([C:7]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[C:5]2[O:36][CH:38]=[N:4][N:3]=2)[N:15]([CH3:35])[C:16](=[O:34])[N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)[C:18]=1[CH3:23])(=[O:37])[CH3:21]
Reactant: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Reactant: [OH-]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C=O
Solvent: ClCCl
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1-c1nnco1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid formyl hydrazide (intermediate 11) (30.0 mg, 0.06 mmol)) is suspended in dichloromethane (1 mL) and (methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide (Burgess reagent)(35.8 mg, 0.15 mmol) is added. The mixture is stirred at room temperature for 3 days. Additional (methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide (Burgess reagent)(35.8 mg, 0.15 mmol) is added and the reaction is continued for 2 h at 40° C. The solvent is removed under reduced pressure and purification is performed by reversed phase HPLC. Yield: 4 mg; ESI mass spectrum [M+H]+=482; Retention time HPLC: 1.02 min (HPLC method Z018_S04).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>CCOC(C)=O>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][CH2:3]2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@@](O)(C(=O)N1CCC(N)CC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)N1CCC(NC(=O)c2ccc(C#N)cc2)CC1)C(F)(F)F
Yield: 36.6 %

Procedure:
To a solution of (R)-[4-amino-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine] (Example 21, 170 mg, 0.71 mmol) and triethylamine (0.12 mg, 0.86 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzoylchloride (130 mg, 0.78 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc/DCM as eluent to give the title compound as a solid (97 mg, 0.26 mmol). NMR: 1.45 (m, 2H), 1.65 (s, 3H), 2.1 (m, 2H), 3.05 (m, 2H), 4.2 (m, 1H), 4.4-4.6 (m, 2H), 5.1 (s, 1H), 6.2 (d, 1H), 7.65 (d, 2H), 7.8 (d, 2H); m/z 368.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19](Br)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)Cl.[CH3:68][O:69][C:70]1[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=1[NH2:72]>O1CCOCC1.CCN(CC)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([NH:72][C:71]5[CH:73]=[CH:74][CH:75]=[CH:76][C:70]=5[O:69][CH3:68])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1N
Reactant: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccccc1Nc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 150 °C

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide (72 mg, 0.2 mmol) in dioxane (0.400 mL), XANTPHOS (2.3 mg, 0.004 mmol), KtBuO (31 mg, 0.28 mmol), (DPPF)2PdCl2.CH2Cl2 (3.00 mg, 0.004 mmol), and 2-methoxyaniline (30 mg, 0.24 mmol), and Et3N (0.200 mL) were added. The reaction mixture was heated to 150° C. in a microwave reactor for 10 minutes. The resulting material was cooled to room temperature. The crude product was purified by column chromatography on silica gel to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenylamino)pyridin-3-yl)cyclopropanecarboxamide which was then treated with HCl in MeOH to form the HCl salt (2.3 mg, 0.0053 mmol, 2.7%). ESI-MS m/z calc. 403.2, found; 404.5 (M+1)+Retention time 2.29 minutes.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])CCC.CO.[Na].C(=O)([O-])[O-]>O.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([NH:8][CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]([OH:24])=[O:5])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCCOC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A solution of 0.002 mol. of N-benzyloxycarbonyl-2-n-butoxyglycine n-butyl ester is stirred with 10 ml. of methanol and 10 ml. of5% aqueous sodium bicarbonatesodium carbonate solution for 5 hours at 25°. The reaction mixture is then diluted with water and shaken with ethyl acetate. The layers are separated and the aqueous layer is acidified to pH 2.0 and extracted with ethyl acetate containing 10% ethanol. The extracts are dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[N:11]=[C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cccc(-n2cccn2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.O>[CH2:1]([NH:8][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 5.358 g (0.05 mole) of benzylamine and 7.755 g (0.06 mole) of N,N-diisopropylethylamine in 80 mL of CH2Cl2 at room temperatue was added slowly 11.365 g (0.055 mole) of 4-methoxybenzenesulfonyl chloride. The resulting mixture was stirred for 18 hr at room temperature and diluted with water. The organic layer was separated, washed with NaHCO3, water, brine, dried over MgSO4, filtered and concentrated. The residue was boiled in CH2Cl2 :Hexane (1:4), cooled and filtered to provide 11.79 g (85%) of the desired product as a cream solid.
Reaction SMILES: C(OC(=O)NCCNC([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)C(C)C)(C)(C)C.N[CH:36]([C:40]1[N:49]([CH2:50][C:51]2[CH:56]=CC=C[CH:52]=2)[C:48](=[O:57])[C:47]2[C:42](=CC(Cl)=C[CH:46]=2)[N:41]=1)C(C)C.[C:59](OC(=O)NCC=O)(C)(C)C.C(O[BH3-])(=O)C.[Na+]>>[CH2:25]([N:24]1[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:50]([N:49]1[C:48](=[O:57])[C:47]([CH3:46])([CH3:59])[CH2:42][NH:41][CH2:36][CH2:40]1)[CH:51]([CH3:52])[CH3:56])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCC(C)(C)C1=O

Procedure:
Preparation of {2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester: Following the procedure of Example 1b, 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one, (2-oxo-ethyl)-carbamic tert-butyl ester and sodium acetoxyborohydride gave the title compound as a white solid: MS (ES) m/e 485.2 (M+H)+.