Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(C(S(O[CH2:30][CH2:31][Cl:32])(=O)=O)=O)=CC=1>C(C(C)=O)C>[Cl:32][CH2:31][CH2:30][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Cc1ccc(C(=O)S(=O)(=O)OCCCl)cc1
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NS(=O)(=O)c1ccccc1OCCCl
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 2-hydroxyphenylsulfonamide, 7.9 g of potassium carbonate, 13.3 g of 2-chloroethyl p-toloylsulfonate and 80 ml of ethylmethylketone is refluxed for 40 hours. The reaction mixture is cooled to room temperature, filtrated and evaporated to dryness. From the oily residue crystallise after addition of a small portion of methylene chloride 7.0 g of 2-(2-chloroethoxy)-phenylsulfonamide, m.p. 110° C.
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[O:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[OH:46][C:40]([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[O:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=O)o3)cc(-c3ccncc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=O)o3)cc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a 100 ml flask containing (S)-tert-butyl 1-oxo-1-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-6-(pyridin-4-yl)indolin-1-yl)-3-phenylpropan-2-ylcarbamate was added 20 ml of DCM and 10 ml of TFA. The reaction was stirred at room temperature for 6 hours at which time the solvent was removed with a stream of nitrogen to give (S)-5-(1-(2-amino-3-phenylpropanoyl)-6-(pyridin-4-yl)indolin-4-yl)-1,3,4-oxadiazol-2(3H)-one TFA salt 57.1.C (97 mg, 100% yield), which was used in the next step with no further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C>[Cl:19][C:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][C:7]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(C(C)C)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)c1n[nH]c(C(C)C)c1Cl
Temperature: 80 °C

Procedure:
Following protocol L, a the solution of 3,5-diisopropyl-pyrazole (0.5 g, 3.57 mmol) in DMF (10 mL) was added NCS (0.72 g, 5.3 mmol) in portions under vigorous stirring. The reaction mixture was then heated at 80° C. for 14 h and then the reaction was quenched with water. It was then extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine. The organic extracts were combined and dried with Na2SO4 and finally evaporated to give the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][OH:35].[ClH:36]>CN1CCCC1=O.ClCCl.CO.O1CCOCC1.O>[ClH:1].[ClH:36].[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][OH:35])[CH:11]=[CH:10]2
Reactant: NCCNCCO
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(NCCNCCO)ccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (170 mg) and potassium carbonate (350 mg) in N-methylpyrrolidinone (4 mL) was added 2-[(2-aminoethyl)amino]-ethanol (500 μL). The mixture was heated at 120° C. for 5 hours after which it was cooled and poured into water. The resulting solid was isolated by filtration, dried and suspended in dichloromethane (5 mL). The suspension was then treated with di-tert-butyl dicarbonate (220 mg) and triethylamine (200 μL) and stirred for 2 hours. The mixture was poured into water and extracted with dichloromethane (3×20 mL). The combined organic layers were dried, filtered and concentrated. Purification (SiO2, methanol:dichloromethane solution 2.5:97.5 as eluant) yielded the desired isomer which was then dissolved in dichloromethane (5 mL) and methanol (0.5 mL), and treated with hydrochloric acid in 1,4-dioxane (4M, 1 mL) for 1 hour. The resultant suspension was evaporated to dryness and recrystallised from methanol/ethyl acetate to give the title compound as a colourless solid (65 mg).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C=O)C>[Cl:10][C:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccccc1
Yield: 92.8 %

Procedure:
α-Chlorobenzaldoxime was prepared according to the method described in Part A of Example 595 by reacting benzaldoxime (11.5 g, 94.9 mmol) in DMF (20 mL) with N-chlorosuccinimide (12.6 g, 94.9 mmol). α-Chlorobenzaldoxime (13.7 g, 93%) was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:31]2[C:32]([CH3:43])=[C:33]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(C)(C)C.ClCCl>ClCCl>[CH3:43][C:32]1[C:31]2[C:26]([O:25][CH2:24][CH2:23][CH2:22][NH:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:27][CH:28]=[CH:29][C:30]=2[O:34][C:33]=1/[CH:35]=[CH:36]/[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1c(C=Cc2ccccc2)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(/C=C/c2ccccc2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 10% trifluoroacetic acid in dichloromethane [3-(3-methyl-2-styryl-benzofuran-4-yloxy)-propyl]-pyridin-3-ylmethyl-carbamic acid tert-butyl ester (15 mg) in dichloromethane (1 ml) was added with ice-cooling. After 3 hours, the mixture was quenched with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give a colorless solid (7 mg, 58%). ESI-MS: m/z 399 (MH+); 1H-NMR (CDCl3): δ 2.12 (2H, s), 2.37 (3H, s), 2.94 (2H, t, J=6.9 Hz), 3.91 (2H, s), 4.14 (2H, t, J=5.9 Hz), 6.57 (1H, d, J=7.6 Hz), 7.02-7.28 (5H, m), 7.37 (2H, t, J=7.6 Hz), 7.53 (2H, d, J=7.6 Hz), 7.73 (2H, d, J=7.9 Hz), 8.52 (1H, d, J=4.6 Hz), 8.61 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=2O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=3[O:26]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)Cc2cccc(C(C)(C)C)c2O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(C(C)(C)C)c3O2)cc1
Yield: 88.8 %

Procedure:
Treatment of (±)-3-(3-tert-butyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (14.66 g, 0.039 mol) with triphenylphosphine (11.18 g, 0.043 mol) and diethylazodicarboxylate (7.42 g, 0.043 mol) generally according to the procedure described for Intermediate 5 afforded 12.48 g (89%) of (±)-(7-tert-butyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C20H24O4S: C, 66.64; H, 6.71. Found: C, 66.28; H, 6.95.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[NH:25][C:26](=[O:42])[CH2:27][NH:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:15].CC(C1C=CC=C(C(C)C)C=1NC(=O)CNCC(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH3:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26](=[O:42])[CH2:27][N:28]([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1)=[S:11])[CH:29]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:13]
Reactant: CN(C)c1ccc(N=C=S)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=S)Nc1ccc(N(C)C)cc1)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 80 an appropriate amount of 4-dimethylaminophenylisothiocyanate was substituted for ethyl isocyanato acetate and an appropriate amount of the product of Example 4 was substituted for the product of Example 70 and the general procedure of Example 80 was followed the title compound was obtained. Total yield, 0.38 g (33%).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13]CC1C=CC=CC=1)=[CH:8][CH:7]=2)(=[O:3])[NH2:2]>CO.[Pd]>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([OH:13])=[CH:8][CH:7]=2)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc2cc(O)ccc2[nH]1
Yield: 100 %

Procedure:
2-Carbamoyl-5-benzyloxy-1H-indole (1 g; 3.35 mmol) in solution in methanol (60 ml) was hydrogenated on 10% Pd/C (0.28 g) for 2 hours. After filtration on celite the solvent was evaporated to give 2-carbamoyl-5-hydroxy-1H-indole which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:22]=[O:23])C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:22]=[O:23])=[CH:4]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCn1ccc2ccc(OC)cc21
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) is dissolved in DMF (1.5 mL). This is added dropwise to an ice-cold solution of POCl3 (500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperature for 90 minutes, the reaction mixture is re-cooled in an ice bath and is slowly quenched with 6N NaOH (4 mL). The reaction mixture is partitioned between EtOAc and H2O. Purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) yields 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde (849 mg, 81%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([CH2:43][OH:44])=[C:38]([O:45][C@H:46]([CH2:48]C=C)[CH3:47])[CH:37]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:30]([O:29][C@@H:23]([C:12]1[C:13]([CH3:22])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:34])([O:4][CH2:1][CH:2]=[CH:3][CH2:47][C@H:46]([CH3:48])[O:45][C:38]2[CH:37]=[C:36]([F:35])[C:41]([F:42])=[CH:40][C:39]=2[CH2:43][O:44][CH2:20]3)[CH2:6][CH2:7]1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1CO
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1cc(F)c(F)cc1COC3
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)c(F)cc1COC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.171 mmol) and (S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.047 g, 0.205 mmol) in DMF (2 mL) was added sodium hydride (10.26 mg, 0.257 mmol) and the mixture was stirred at rt. After stirring for 4 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The amber oil was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV). The resulting impure amber oil (11.4 mg, 0.017 mmol) was taken up in DCE (4 mL). Hoveyda-Grubbs catalyst 2nd generation (2.72 mg, 4.34 μmol) then copper(I) iodide (3.31 mg, 0.017 mmol) were added and the mixture was stirred at 90° C. After 3 h, the mixture was cooled to rt and filtered and concentrated. The residue was purified by prep HPLC to give ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetate (3.0 mg, 4.57 μmol, 27% yield). LCMS (M+H) calcd for C35H47F2N4O6: 657.34. found: 657.5.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:18]([CH:20]([CH2:23][CH3:24])[CH:21]=[O:22])[CH3:19].[NH4+].[Cl-]>CCOCC>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:21]([OH:22])[CH:20]([CH2:23][CH3:24])[CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C=O)CC
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(CC)C(O)c1nccn1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a chilled reaction vessel at −45° C. containing 1-benzyl-1H-imidazole (3.0 g, 19.0 mmol) in Et2O (100 mL) was added a solution of n-butyllithium (2.5M in hexanes, 10.8 mL, 26.9 mmol) dropwise. After 30 min, the reaction vessel was cooled to −78° C. and 2-ethylbutyraldehyde (2.8 mL, 22.8 mmol) was added dropwise. The reaction mixture was warmed to 0° C. and stirred for 15 min, then poured into sat. aqueous NH4Cl and extracted with Et2O. The organic layer was washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. The resulting yellow oil was purified by column chromatography (SiO2, EtOAc/hexane, 3:2, then 7:3) to yield a clear oil in 69% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:25]3[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(=O)C1C=CC=C(C2N3C=CN=C(Cl)C3=C(C3C=CC=C(OCC4C=CC=CC=4)C=3)[N:43]=2)C=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:43][C:20]1[C:19]2[N:18]([C:17]([C:25]3[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)c1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)c1
Reactant: OCc1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nccn2c(-c3cccc(CO)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Reaction time: 2 h
Yield: 71 %

Procedure:
{3-[1-(3-Benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]-phenyl}-methanol: To a solution of 3-[1-(3-benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]-benzoic acid methyl ester (552 mg, 1.17 mmol) in THF (25 mL), cooled to 0° C., 1M LiAlH4 (880 μL, 797 mg, 0.880 mmol) was added, under N2, and the reaction solution was vortexed for 2 h. Upon addition, the reaction mixture changed from yellow to dark green in color. The reaction was quenched with potassium sodium tartrate sat. aq. sol. (25 mL), extracted with EtOAc (3×20 mL), washed with brine (1×40 mL), dried over MgSO4, and filtered. The crude material was purified by filtration through a plug of silica gel plug [eluting with EtOAc:CH2Cl2 1:1 (400 mL)] and concentrated, affording 366.3 mg (71%, 0.829 mmol) of the title compound, as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 4.82 (d, J=6.0 Hz, 2H), 5.15 (s, 2H), 7.05-7.11 (m, 1H), 7.32-7.43 (m, 7H), 7.44-7.49 (m, 2H), 7.52-7.61 (m, 2H), 7.73-7.78 (m, 1H), 7.87 (s, 1H), 8.05 (d, J=4.8 Hz, 1H); MS (ES+): m/z 441.9/443.9 (100/38) [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>ClCCl>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-6-chloropyridine (3.0 g, 23.3 mmol) in dichloromethane (45 mL) under argon was added triethylamine (4.10 mL, 29.2 mmol) and the reaction cooled to 0° C. (ice bath). A solution of trimethylacetyl chloride (3.16 mL, 25.7 mmol) in dichloromethane (10 mL) was added dropwise over 20 min before stirring for 30 min at 0° C. The reaction was brought up to rt and stirred for a further 5 h, then water (30 mL) was added. The organics were separated and washed with Na2CO3 solution (2×50 mL), dried (MgSO4) and solvent removed in vacuo. Purification by column chromatography (SiO2, CH2Cl2) gave the title compound. m/z (ES+)=213.04 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>CN(C=O)C>[Br:23][CH:24]([CH3:28])[C:25]([NH:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:26]
Reactant: NC(=O)c1cnn(C2CCOCC2)c1N
Reactant: CC(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)Nc1c(C(N)=O)cnn1C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of C2 (5.0 g, 23.8 mmol) and triethylamine (3.65 mL, 26.2 mmol) in anhydrous DMF (50 mL) was cooled in an ice bath and treated drop-wise with 2-bromopropanoyl bromide (5.4 g, 25 mmol). The mixture was stirred at 0° C. for 30 mins, warmed to room temperature and stirred at ambient temperature for an additional 2 h. The reaction was partitioned between EtOAc (200 mL) and aqueous 2N hydrochloric acid (500 mL); the organic phase was washed with saturated aqueous sodium bicarbonate solution (400 mL), saturated aqueous sodium chloride solution (200 mL) and dried over sodium sulfate. Filtration and concentration of the filtrate provided crude C24 as an orange residue, which was used in the next step without purification,
Reaction SMILES: C([O:8][C:9]([CH:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][CH:38]=1)[C:17]([C:19]1[CH:20]=[C:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2)=[O:18])[CH3:12])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([CH:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][CH:38]=1)[C:17]([C:19]1[CH:20]=[C:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2)=[O:18])[CH3:12])([OH:10])=[O:8]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(C)C(=O)OCc3ccccc3)c2)c2ccccn12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(C)C(=O)O)c2)c2ccccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of ethyl 4-[1-[3-[(1-benzyloxycarbonylethyl)amino]benzoyl]indolizin-3-yl]butyrate (0.20 g) in ethanol (10 ml) was added 10% palladium on carbon (0.1 g). The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. Removal of catalyst and evaporation of solvent gave ethyl 4-[1-[3-(1-carboxyethylamino)benzoyl]indolizin-3-yl]butyrate (0.15 g) as yellow powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1(=O)CCN(c2nc(N3CCNCC3)nc3c(NCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-(1,1-dioxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 213°-215° C.) and piperazine.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([C@H:30]3[CH2:35][CH2:34][C@H:33]([C:36]([NH2:38])=O)[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[N:28][C:27]([C@H:30]3[CH2:31][CH2:32][C@H:33]([C:36]#[N:38])[CH2:34][CH2:35]3)=[N:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCc1ccc(-c2cnc([C@H]3CC[C@H](C(N)=O)CC3)nc2)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCc1ccc(-c2cnc([C@H]3CC[C@H](C#N)CC3)nc2)cc1
Temperature: 55 °C

Procedure:
6.0 Ml. of benzenesulfonyl chloride are added dropwise while stirring to a suspension of 10.8 g. of trans-4-[5-(p-n-heptylphenyl)-2-pyrimidinyl]cyclohexane carboxamide in 150 ml. of pyridine. The mixture is then warmed to 55° C. for 2 hours in an oilbath. The mixture is poured into ice-water and the product is taken up in methylene chloride. The extract is washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The crude product is chromatographed on a column of 300 g. of silica gel with toluene/5% acetone (v/v). The fractions which are pure according to thin-layer chromatography are combined and evaporated. The residue is dissolved in hexane, filtered hot with active carbon and recrystallized. The crystallizate is dried in vacuo overnight. There is obtained trans-4-[5-(p-n-heptylphenyl)-2-pyrimidinyl]cyclohexane carbonitrile; melting point 83.5° C., clearing point 160° C.
Reaction SMILES: C(O[C:4](=[NH:15])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][NH2:28])=[O:26]>C(Cl)(Cl)Cl>[NH2:15][C:4](=[N:28][NH:27][C:25]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=1)=[O:26])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: NNC(=O)c1cc2ccccc2o1
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1cc2ccccc2o1
Yield: 59.8 %

Procedure:
3.4 g (0.0125 Mol) of 2-(phenylsulfonyl)-ethanimidic acid ethyl ester was stirred together with 2.2 g (0.015 mol) benzofuran-2-carboxylic acid hydrazide in 80 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. 2.67 g of benzofuran-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as off-white crystals. Mp.: 205-220° C.