Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (50 mg, 0.162 mmol) was dissolved in dry DCM under nitrogen atmosphere. 4-chloro-3-trifluoromethylphenylisocyanate (43 mg, 0.195 mmol, 1.2 eq) was added, the mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluant: 100% ethyl acetate) to give 64 mg (75%) of 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-urea as white powder.
Reaction SMILES: C([NH:8][C:9]([N:18]1[CH:22]=[CH:21][CH:20]=N1)=[N:10]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.NCCC[CH2:27][CH2:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][CH:33]=[C:34]2[C:39]=1[O:38][C:37](=[O:40])[CH:36]=[C:35]2[NH:41][C:42]1[C:47]([Cl:48])=[CH:46][N:45]=[CH:44][C:43]=1[Cl:49].FC(F)(F)C(O)=O>ClCCl>[Cl:49][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([Cl:48])[C:42]=1[NH:41][C:35]1[C:34]2[C:39](=[C:30]([O:29][CH2:28][CH2:27][CH2:20][CH2:21][CH2:22][NH:18][C:9]([NH2:8])=[NH:10])[C:31]([O:50][CH3:51])=[CH:32][CH:33]=2)[O:38][C:37](=[O:40])[CH:36]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCNC(=N)N
Reaction time: 0.5 h

Procedure:
N,N′-Di-Boc-1H-pyrazole-1-carboxamidine (40 mg, 0.13 mmol) was added to a mixture of 8-(5-aminopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (40 mg, 0.09 mmol, Example 68) and dichloromethane (3 mL). After stirring for 30 min, trifluoroacetic acid (0.3 mL) was added. After an additional 19 h, the reaction was concentrated and purified by reverse-phase HPLC (1:9→3:2; acetonitrile:water) to give to give 1-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)pentyl)guanidine: 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 9.60 (s, 1H), 8.82 (s, 2H), 7.98 (d, 1H), 7.57 (t, 1H), 7.50-6.70 (br, 4H), 7.21 (d, 1H), 4.63 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.11 (m, 2H), 1.70 (m, 2H), 1.52 (m, 4H); MS (ESI): 479.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([CH:5]=[C:6]([Cl:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C@@H:3]1[C:15](O)=[O:16].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4]([CH:5]=[C:6]([Cl:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C@@H:3]1[C:15]([Cl:21])=[O:16]
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 80 °C

Procedure:
21.5 g (0.07 mol) of (±)-cis/trans-2,2-dimethyl-3-(2-chloro-3,3,4,4,4-pentafluoro-1-butenyl)-cyclopropane-1-carboxylic acid were dissolved in 150 ml of carbon tetrachloride, and 50 ml of thionyl chloride were added. The mixture was then warmed to 80° C. for 1 hour, while stirring. After distilling off the excess thionyl chloride and the solvent, the residue was distilled under a high vacuum. 21 g of (±)-cis/trans-2,2-dimethyl-3-(2-chloro-3,3,4,4,4-pentafluoro-1-butenyl)-cyclopropane-1-carboxylic acid chloride of boiling point 50°-54° C./0.3 mbar were obtained. ##STR10##
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(C(N)=O)cc1)nn2C1CCCC1
Yield: 90.5 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (120 mg) obtained in Step C of Example 12, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (122 mg), tetrakis(triphenylphosphine)palladium(0) (38.0 mg) and 2M aqueous sodium carbonate solution (0.821 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in ethyl acetate (10 ml) were added 3-phenylpropionyl chloride (168 ml, 1.13 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (302 mg, 86%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1)=O>>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[CH:21]=[C:20]3[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[N:18][NH:19]3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=Cc1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Yield: 20.9 %

Procedure:
The title compound (17 mg, 21%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using indolin-2-one (26.6 mg, 0.2 mmol) and (E)-4-(2-(6-formyl-1H-indazol-3-yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 12.90 (s, br, 1H), 10.64 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.80 (s, 1H), 7.74 (d, J=16.8 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H partially overlapping with the singlet at 7.62), 7.62 (s, 1H partially overlapping with the doublet at 7.63), 7.24 (t, J=7.4 Hz, 1H), 6.91-6.82 (m, 2H); MS ESI 408.2 [M+H]+, calcd for [C25H17N3O3+H]+ 408.1.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: O=c1occ(CBr)o1
Reactant: Fc1ccc(S)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1occ(CSc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.8 g of 4-fluorobenzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v)]. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.52 g of the captioned compound as pale yellow crystals.
Reaction SMILES: [Li][C@H:2]1[CH2:6][CH:5]([C:7](O)=O)N([Li])[C:3]1=O.[Li][CH2:13][CH2:14][CH2:15][CH3:16]>CCOCC>[CH:2]1([CH:15]([C:14]2[CH:13]=[CH:5][CH:6]=[CH:2][CH:3]=2)[CH3:16])[CH:6]=[CH:5][CH:7]=[CH:3]1
Reactant: [Li]CCCC
Reactant: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: CCOCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 176.2 %

Procedure:
To a solution of 0.77 g of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (6 mmol) in 40 mL of ether was added 7.8 mL of n-BuLi (1.6 m solution in hexanes, 13 mmol) at 0° C. This solution was stirred for 30 min at room temperature. The solvent was removed under vacuum and 25 mL of ether added. 6-Methyl-6-phenylfulvene, 1.0 g, (6 mmol) in 5 mL of ether was added dropwise at -78° C. and the color of the reaction mixture turned green. The resulting solution was stirred for 7 h at -78° C. and the color of the reaction mixture turned yellow. Water, 25 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 0.9 g (89% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =2.0° (CHCL3), 5.8% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16]([CH3:17])=[O:31])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)O)cc1Cl
Reaction time: 5 h

Procedure:
In DCM (20 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (200 mg, 0.59 mmol). The solution was cooled in an ice bath and m-CPBA (101 mg, 0.59 mmol) was added. The reaction was conducted at ambient temperature for 5 h, followed by addition of water and extraction with DCM. The organic phase was dried and concentrated to give a solid which was used in the subsequent procedure without further purification.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH2:25]([C:27]1[O:28][C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:30]([C:32](Cl)=[O:33])[N:31]=1)[CH3:26]>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:32]([C:30]1[N:31]=[C:27]([CH2:25][CH3:26])[O:28][C:29]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:33])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Reactant: CCc1nc(C(=O)Cl)c(-c2ccccc2)o1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-ethyl-5-phenyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.25. LC-MS-conditions 02: tR=1.11 min, [M+H]+=482.83.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1CC2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:32]([N:34]1CC(C#N)CC1C(=O)NCC(C1C=CC(Br)=CC=1)=O)=O)(C)(C)C.C(OC(N1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:26]([C:32]#[N:34])[CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[CH2:6][CH:7]1[CH2:9][CH2:8]1)[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[C:6]([CH:7]1[CH2:9][CH2:8]1)=[CH:14][N:15]([CH3:17])[CH3:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CC1CC1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=O)C(=CN(C)C)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
A mixture of 3-cyclopropyl-2-oxo-propionic acid ethyl ester (6.4 mmol, 1.0 g) and dimethylformamide dimethylacetal (12.8 mmol, 2.0 mL) are combined and stirred at room temperature for 18 hours. The reaction is concentrated under reduced pressure to yield the title compound (1.38 g, 100%). LC-MS: 212.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH:15]=O)[C:7]=2[N:6]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH2:15][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:7]=2[N:6]=1
Reactant: C1CCNC1
Reactant: CCC(CC)c1ccc(C=O)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(CC)c1ccc(CN2CCCC2)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a mixture of 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde (93 mg, 0.23 mmol), pyrrolidine (33 mg, 0.46 mmol), acetic acid (0.5 ml) and ethyl acetate (1.5 ml) was added sodium triacetoxyborohydride (244 mg, 1.15 mmol) and the reaction mixture was stirred at room temperature for 1 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with a 5% ethyl acetate/n-hexane to give 100 mg (0.22 mmol, 94%) of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH3:14])[N:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCOCC1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)=[N:3][C:4]([C@@H:13]([NH2:15])[CH3:14])=[CH:5]2
Reactant: CN1CCNCC1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Solvent: C1COCCO1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(N2CCN(C)CC2)n1
Temperature: 25 °C

Procedure:
A solution of (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate 69 (250 mg, 0.539 mmol, 1.0 eq) and 1-methylpiperazine (108 mg, 1.079 mmol, 2.0 eq) in 1,4-dioxane (5 mL) was stirred at reflux overnight. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3.3% MeOH-DCM) to afford the product (S)-1-(8-chloro-1-(4-methylpiperazin-1-yl) isoquinolin-3-yl)ethanamine 95.
Reaction SMILES: [CH3:1][C:2]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]1([CH3:18])[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3]2.C(=O)(O)[O-].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C@@:10]2([CH3:18])[CH2:11][C:12]3[C:17]([C@@:2]12[CH3:1])=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:26])[CH3:25]
Reactant: CC12Cc3ccccc3C1(C)Nc1ccccc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1c2ccccc2[C@@]2(C)Cc3ccccc3[C@@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4b,5,9b,10-tetrahydro-4b,9b-dimethylindeno[1,2-b]indole, (0.2 g, 0.85 mmol) was dissolved in acetic anhydride (1 cm3) and the solution stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and stirred for a further 1/2 hour. The mixture was then extracted with ether (3×15 cm3) and the combined organic extracts collected washed with brine, dried (Na2SO4) and evaporated to yield the title compound as an oil. This was purified by flash chromatography on silica gel eluting with 5-7% ethyl acetate/60°-80° petrol, to yield a colourless solid. Yield: 0.15 g, 64% .M.p. 81° C. 1H NMR (CDCl3) δ: 7.82 (1H, s), 6.99-7.29 (7H, m), 3.26 (1H, d, J=15.9 Hz), 2.97 (1H, d, J =15.9 Hz), 2.42 (3H, s), 1.77 (3H, s), 1.25 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(Cl)ccc2nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1nc2cc(Cl)ccc2nc1NN

Procedure:
A mixture of 4.9 g. (0.02 mole) of 2,6-dichloro-3-methoxyquinoxaline and 2.7 g. (0.053 mole) of hydrazine hydrate (2.6 ml.) in 75 ml. of ethanol was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). Upon completion of this step, the resulting mixture was filtered and the recovered precipitate was washed with ethanol to ultimately afford 4.4 g. (98%) of pure 6-chloro-2-hydrazino-3-methoyquinoxaline, m.p. 175°-179° C. (decomp.). Mass Spectrum: m/e, 224 (P); m/e, 226 (P+2).
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.[Cl:5][SiH:6]([Cl:8])[Cl:7]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:5][Si:6]([Cl:8])([Cl:7])[CH2:2][CH2:3][Si:6]([Cl:8])([Cl:7])[Cl:5]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCCCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Yield: 48.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.44 g (1.50 mmol) of tetrabutylphosphonium chloride, 0.74 g (7.5 mmol) of 1,2-dichloroethane, and 10.16 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 1.09 g of 1,2-bis(trichlorosilyl)ethane (yield; 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:21][C:22](O)=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:23]=[C:22]1[CH2:21][C@@H:16]2[C@H:15]([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@H]2CCCC[C@@H]2CC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C[C@H]3CCCC[C@@H]32)CC1
Temperature: 25 °C

Procedure:
((1R,2S)-2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}cyclohexyl)acetic acid was dissolved in DMF (3 mL) and diisopropyl ethylamine (50 μL) and HATU (0.1 g, 0.26 mmol) was then added and the mixture stirred at room temperature over night. The solvent was then removed under reduced pressure and the mixture was diluted in dichloromethane. Washed with 1N NaOH and with brine and the solvent was then removed under reduced pressure to give the tile compound. MS (M+1): 323.24