Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([C@@H:14]([NH2:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([NH:16][C@H:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH:9]=1)[CH3:15])=[O:23]
Reactant: C[C@H](N)c1cccc(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Mixture of (S)-1-(3-morpholin-4-yl-phenyl)-ethylamine hydrochloride, Preparation 21 (50 mg, 0.21 mmol), 2-fluorocinnamic acid (37 mg, 0.23 mmol), EDC (79 mg, 0.41 mmol), DMAP (25 mg, 0.21 mmol), triethylamine (0.11 ml, 0.82 mmol) in dichloromethane (1 mL) was stirred at room temperature for 10 hours. The reaction mixture was concentrated under vacuum and purified by filtering through 2 g silica-gel syringe with 80% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37][CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)nc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)nc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.91 g) in methylene chloride (27.3 ml) was added dropwise a solution of m-chloroperbenzoic acid (303 mg) in methylene chloride (18.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[(3-pyridinylmethyl)sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 274) (258 mg).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([NH2:30])[CH:17]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:38]1([CH2:51][O:52][C:53](Cl)=[O:54])[C:50]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([NH:30][C:53]([O:52][CH2:51][C:38]3[C:50]4[CH2:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:42]=4[CH:41]=[CH:40][CH:39]=3)=[O:54])[CH:17]=2)=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3ccccc3)c(N)c2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3ccccc3)c(NC(=O)OCc3cccc4c3Cc3ccccc3-4)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
4-(3-Amino-4-benzoylphenoxymethyl)phenoxyacetic acid allyl ester (4.74 g, 11.4 mmol) and pyridine (1.09 g, 13.7 mmol, 1.2 equiv) were dissolved in 60 mL of CH2Cl2. The resulting yellow solution was cooled to 0° C., and fluorenylmethoxycarbonyl chloride (2.65 g, 1.14 mmol, 1.05 equiv) was added. The resulting solution was stirred at 0° C. for 15 min and then at ambient temperature for 1 h. The solution was diluted with CH2Cl2 (150 mL), extracted twice with 1N aqueous sodium bisulfate (100 mL), once with dilute aqueous sodium chloride (100 mL), and then concentrated to give a yellow foam. The unpurified product was crystallized from CH2Cl2 and hexanes to give 4.87 g (79% yield) purified material as a white solid: mp 96.5°-97.5° C. Rf 0.45 (CH2Cl2); IR (film from CH2Cl2, partial) 3230(b), 1740, 1610, 1575 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 4.32 (t, 1, J=7.4), 4.44 (s, 1, J=0.5), 4.71 (dd, 2, J=1.2, 5.9), 5.11 (s, 2), 5.26 (dd, 1, J=1.2, 10.4), 5.30 (dd, 1, J=1.4, 17.2), 5.85-598 (m, 2), 6.58 (dd, 2, J=2,5m 8.9) 6.92 (d, 2, J=8.8, 6.92 (q, 2, J=4.8, 9.6), 7.30-7.59 (m, 8), 7.63-7.70 (m,5), 7.76 (d, 2, J=8.9), 7.77 (d, 2, J=7.5), 8.29 (d, 1, J=2.3). 13C NMR (75.5 MHz, CDCl3) δ 47.3, 65.6, 66.2, 67.9, 70.0, 104.4, 109.6, 115.2, 115.8, 119.5, 120.4, 125.6, 127.5, 128.1, 128.8, 129.6, 129.8, 131.7, 131.9, 137.6, 140.0, 141.6, 144.1, 144.6, 154.1, 158.5, 164.1, 167.8, 199.1. Anal. Calcd for C40H33NO7 : C, 75.10; H, 5.20; N, 2.19. Found: C, 75.21; H, 5.33; N, 2.28.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)#[CH:2].[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].CC(C)([O-])C.[K+]>>[C:10]([O:14]/[CH:2]=[CH:1]\[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#Cc1ccc(C)cn1
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(/C=C\OC(C)(C)C)nc1

Procedure:
To the solution of 2-ethynyl-5-methylpyridine (12-2) (1.38 g, 11.8 mmol) in tert-butyl alcohol (4.734 g, 63.9 mmol) was added potassium tert-butoxide (531 mg, 4.7 mmol) under nitrogen. The solution was heated to reflux for overnight. The solvent was removed under reduced pressure. The residue was purified by silca gel chromatography with the gradient eluent (PE/EA/NEt3=10/1/1%; 5/1/1%). The product (Z)-2-(2-tert-butoxyvinyl)-5-methylpyridine (12-3) was obtained as yellow oil (1.40 g, 62%) and by product was (E)-2-(2-tert-butoxyvinyl)-5-methylpyridine (0.3 g, 13%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH:16]([CH3:18])[CH3:17])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:20]
Reactant: CC(C)c1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)c1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-isopropyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (3.011 g; 7.941 mmol) in DCM (75 ml) was added slowly 4N HCl in dioxane (40 ml; 160 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 2 h45. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-isopropyl-imidazol-1-yl)-ethylamine was obtained as a colorless solid (2.720 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.19 min.; [M+H]+=280.17 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH:25]3[C:34]4[C:29](=[C:30]([OH:35])[CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH:25]3[C:34]4[C:29](=[C:30]([O:35][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(-c2nc(C3CCCN3C3CCCc4c(O)cccc43)oc2-c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2N1CCCC1c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.4 %

Procedure:
To a solution of 1-[2-[4,5-bis(4-methylphenyl)oxazol-2-yl]pyrrolidin-1-yl]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.13 g) and ethyl bromoacetate (0.10 g) in DMF (5 ml) was added K2CO3 (0.13 g). After being stirred for 2 days at room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-[4,5-bis(4-methylphenyl)oxazol-2-yl]pyrrolidin-1-yl]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.13 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C(N(CC)CC)C>C1COCC1.O>[C:27](=[O:28])([O:24][CH2:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH:10]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)[N:18]=3)[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[NH2:29]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CO)cc1OCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(COC(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methanol (0.10 g, 0.31 mmol) in THF (1 mL) cooled to −78° C. was added trichloroacetyl isocyanate (40 μL, 0.47 mmol). The resultant mixture was allowed to warm to 0° C. before triethylamine (0.17 mL) and water (0.3 mL) were added and the mixture stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 547 (0.095 g, 83%). LCMS: RT=3.34 min, [M+H]+=369. 1H-NMR 400 MHz (DMSO-d6): δ 8.39 (1H, d, J=8.24 Hz), 7.92-7.92 (2H, m), 7.11 (1H, dd, J=8.30, 1.71 Hz), 7.02 (1H, d, J=1.63 Hz), 5.88-5.87 (1H, m), 4.99 (2H, s), 4.55-4.49 (4 H, m), 3.29 (2H, s), 1.48 (6H, d, J=6.60 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[N:18]1([CH2:24][CH2:25][O:26][CH2:27][B-](F)(F)F)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[N:18]1([CH2:24][CH2:25][O:26][CH2:27][C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: F[B-](F)(F)COCCN1CCOCC1
Reactant: Brc1cnc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc2ncc(COCCN3CCOCC3)cc2c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 2.6 %

Procedure:
To a mixture of 3-bromoquinoline (80 mg, 0.39 mmol) and 1,4-dioxane (4 ml) were added water (0.4 ml), cesium carbonate (564 mg, 1.7 mmol), [(2-morpholin-4-ylethoxy)-methyl]trifluoroborate (145 mg, 0.58 mmol), palladium (II) acetate (8.6 mg, 0.04 mmol) and 2,2′-bis(diphenylphosphino)1,1′-binaphthyl (48 mg 0.08 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 15 hours. After the reaction mixture was cooled at room temperature, water and ethyl acetate were added to the mixture, followed by filtration using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (3.2 mg, 0.01 mmol, 3.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]([N:17]1[CH2:22][C:21]([CH3:23])=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:19]2[N:34]=[CH:35][C:36]([C:37]#[N:38])=[C:18]12)=[O:16]>CC(C)=O>[CH3:23][C:21]1[CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[C:18]2[N:19]([N:34]=[CH:35][C:36]=2[C:37]#[N:38])[C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Solvent: CC(C)=O
Product: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(c3ccccn3)CC2)C1
Yield: 100.2 %

Procedure:
A mixture of 2 g of 1-(2-pyridinyl)piperazine, 2 g of 4-(chloroacetyl)-4,5-dihydro-6-methyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile and 60 ml of acetone was refluxed on a steam bath for 8 hours and then evaporated. The residue was stirred in water and the solid collected. The solid was dissolved in dilute hydrochloric acid, filtered and the filtrate gasified with dilute ammonium hydroxide. The solid was collected, washed with water and dried in vacuo, giving 2.67 g of the desired product, mp 132°-134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17]>>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9](=[O:18])[CH2:6][C:2]#[N:1])[CH3:17]
Reactant: Nc1cc[nH]n1
Reactant: CCc1ccccc1C(=O)OC
Product: CCc1ccccc1C(=O)CC#N
Yield: 92 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 2-ethyl-benzoic acid methyl ester (2.9 g, 17.6 mmol, 1.0 eq). The crude product was extracted with DCM as a yellow oil and used in the following step without further purification (2.8 g, yield: 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:16][C:17]1([CH3:23])[CH2:21][NH:20][C:19](=[O:22])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[CH3:16][C:17]1([CH3:23])[CH2:21][N:20]([C:2]2[CH:7]=[N:6][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[C:19](=[O:22])[CH2:18]1
Reactant: Brc1ccc(C#Cc2ccccc2)nc1
Reactant: CC1(C)CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)nc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a suspension of 5-bromo-2-phenylethynyl-pyridine (Example 1, step 1) (40 mg, 0.155 mmol), 4,4-dimethylpyrrolidine-2-one (21 mg, 0.186 mmol, 1.2 equiv.), potassium carbonate (64 mg, 0.465 mmol, 3 equiv.) and N,N′-dimethylethylenediamine (1.4 mg, 0.015 mmol, 0.1 equiv.) in 1 ml of dioxane was added under argon atmosphere copper(I)iodide (3 mg, 0.015 mmol, 0.1 equiv.). The mixture was stirred overnight at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were extracted with brine, combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to 30:70. The desired 4,4-dimethyl-1-(6-phenylethynyl-pyridin-3-yl)-pyrrolidin-2-one (30 mg, 67% yield) was obtained as a white solid, MS: m/e=291.1 (M+H30).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[I:18]Cl.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[C:16]([I:18])=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: ClI
Reactant: Oc1cc2cnnc(-c3ccccc3F)n2n1
Solvent: O
Solvent: CC(=O)O
Product: Oc1nn2c(-c3ccccc3F)nncc2c1I
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
To a stirred mixture of 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.5014 g, 2.18 mmol) in glacial acetic acid (10 ml) was added dropwise a 1.0 M solution of iodine monochloride in glacial acetic acid (3.26 ml, 3.26 mmol) and the mixture was stirred at room temperature for a total of 1.25 h. Water (40 ml) was then added and the resulting solid was collected by filtration, washed with water, and dried under vacuum at 60° C. to yield 0.7345 g (95%) of the title compound as a pale brown solid; 1H NMR (360 MHz, d6 -DMSO) δ 7.42-7.49 (2H, m), 7.71 (1H, m), 7.79 (1H, m), 9.26 (1H, s), 12.48 (1H, s); MS (ES+) m/e 357 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:22](=O)(OCC)OCC.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]4[CH2:19][O:20][CH2:22][NH:21]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Reactant: CCOC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(CC4COCN4)cc23)CC1
Temperature: 130 °C
Yield: 66 %

Procedure:
A mixture of the product from step (f) (1.6 g), diethyl carbonate (0.71 g) and potassium carbonate (0.08 g) was heated at 130° C. for 5 hours. The mixture was cooled, taken up in methanol and the insoluble potassium carbonate filtered off. The filtrate was evaporated in vacuo and the residue eluted through a silica column using DCM/EtOH/NH4OH (30:8:1) as eluant to give a colourless foam which was crystallised from isopropanol/ether to give the desired product as a colourless crystalline solid (1.1 g), mp 191°-192° C. 1H NMR and microanalysis as for product of Synthetic Example 4.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:6][CH:5]=1.C([O:26][C:27](=[O:47])[CH2:28][CH2:29][CH:30](OS(C)(=O)=O)[CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(C)(C)C.O>CC(N(C)C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]([CH:30]([CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:29][CH:28]([C:7]([CH3:20])([CH3:8])[CH3:6])[C:27]([OH:26])=[O:47])[N:10]=2)=[CH:20][CH:21]=1
Reactant: CN(CCC(CCC(=O)OC(C)(C)C)OS(C)(=O)=O)Cc1ccccc1
Reactant: O=c1[nH]nc(Cc2ccc(Cl)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(CCC(CC(C(=O)O)C(C)(C)C)n1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3 g sodium hydride (80%, in white oil) are added to 21.6 g 4(4-chlorobenzyl)-1(2H)-phthalazinone in 200 ml dimethylacetamide (DMA) with cooling in an ice bath. 37 g 6-(N-methyl -N-benzylamino )-4-methylsulfonyloxy-caproic acid-t-butyl ester in 80 ml DMA are then added dropwise with cooling and stirring continued for 0.5 hour. The mixture is allowed to warm slowly--overnight--to room temperature and is then heated for 2 hours to 40° C.-50° C. The mixture is hydrolyzed by addition of 200 ml water with ice cooling. The precipitated oil is separated and dissolved in dichloromethane. After extraction twice with water, the organic phase is dried and concentrated. The residue is chromatographed over silica gel (Eluent: dichloromethane/methanol/ammonia 25% 95:4:1). 3.5 g are obtained (yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)=[O:4]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:7]1
Reactant: COC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@H]1CCNC1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Phenylmethyl (3S)-3-{[(methyloxy)carbonyl]amino}-1-pyrrolidinecarboxylate (2.00 g, 7.19 mmol) was dissolved in degassed methanol (20 mL) and Pd/C (0.4 g, 0.376 mmol) was added. The reaction vessel was evacuated and back-filled with hydrogen via a balloon. The reaction was stirred for 2 h after which time the catalyst was removed by filtration through Celite. Evaporation of the solvent yielded methyl (3S)-3-pyrrolidinylcarbamate (0.99 g, 76%) as a clear oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[CH2:20]([O:22][C:23](=[O:32])[C@@:24]([CH3:31])([C:27]([NH:29][CH3:30])=[O:28])[NH:25][CH3:26])[CH3:21]>C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23](=[O:32])[C:24]([N:25]([CH3:26])[C:15]([C:14]1[CH:18]=[CH:19][C:11]([I:10])=[CH:12][CH:13]=1)=[O:16])([CH3:31])[C:27]([NH:29][CH3:30])=[O:28])[CH3:21]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98 %

Procedure:
DIPEA (0.34 mL) and 4-iodobenzoyl chloride (0.13 g) were added to a chloroform (2.3 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.25 g) under ice cooling, and the mixture was stirred for 40 minutes at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by NH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→35/65) to obtain 1-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 10-1, yellow oil) (0.20 g, 72%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CC(=O)O
Reactant: COCCOCCOc1cccc(C=O)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COCCOCCOc1cccc(C=CC(=O)O)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 3-[2-(2-methoxyethoxy)ethoxy]benzaldehyde (9.18 g, 40.9 mmol) in pyridine (70 mL) under nitrogen was added malonic acid (8.69 g, 81.9 mmol) followed by piperidine (4.13 mL, 40.9 mmol). The reaction solution was stirred for 3 h at 85° C. and left stirring over night at room temperature. The reaction solution was concentrated to an oil and left on high vacuum over night to remove the remaining pyridine. To the oil was added ice (120 g) and under vigorous stirring, concentrated hydrochloric acid (13 mL) was added. The mixture was extracted with methylene chloride (3×65 mL) and the combined organic layer was washed with water (60 mL) and brine (60 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The resulting oil was dried in high vacuum to give 10.8 g (99% yield) of the title compound. 1HNMR (300 MHz, DMSO-d6) δ 12.28 (br s, 1H), 7.56 (d, J=16 Hz, 1H), 7.28 (m, 3H), 6.99 (dd, J=8 Hz, J=2 Hz, 1H), 6.56 (d, J=16 Hz, 1H), 4.14 (t, J=5 Hz, 2H), 3.75 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 3.36 (t, J=5 Hz, 2H), 3.25 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(Cl)cc13)CCCNC2=O

Procedure:
The title compound, white solid (72 mg, 80%), MS (ISP) m/z=359.3 [(M+H)+], mp 271° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).