Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:10])[CH2:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:17]/[C:18](/[C:28]([CH2:33][F:34])([CH2:31][F:32])[CH2:29][F:30])=[CH:19]\[C@@H:20]1[C@H:22]([C:23](Cl)=[O:24])[C:21]1([CH3:27])[CH3:26]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:17]/[C:18](/[C:28]([CH2:33][F:34])([CH2:29][F:30])[CH2:31][F:32])=[CH:19]\[C@@H:20]1[C@H:22]([C:23]([O:10][CH:6]2[CH2:7][C:8]([CH3:9])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]2)=[O:24])[C:21]1([CH3:26])[CH3:27]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(CF)(CF)CF)[C@@H]1C(=O)Cl
Reactant: C=CCC1=C(C)CC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(CF)(CF)CF)C2(C)C)C1
Yield: 81 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-ol (190 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (140 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (353 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 382 mg of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 34). Yield 77% nD24 1.4721
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([O:21][C:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1)=[O:23])[CH3:20].C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:19]([O:21][C:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH2:37][N:38]([C:2]3[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[C:5]4[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=4[N:3]=3)[CH2:39][CH2:40][CH2:41]2)=[CH:28][CH:27]=1)=[O:23])[CH3:20]
Reactant: Fc1ccc(Cn2c(Br)nc3ccccc32)cc1
Reactant: CCOC(=O)CCc1ccc(CCN2CCCNCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1
Yield: 85 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole (0.244 g) in n-butanol (1 ml) was added 1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (1.00 g), and the mixture was refluxed for 2 hours. To the reaction mixture was added a saturated aqueous NaHCO3 solution (50 ml), and the mixture was extracted with methylene chloride (30 ml). The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:0.25) as eluent to give a mixture (0.369 g) of 5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane and 5-[2-[4-(2-n-butoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:31][CH2:32]OC>C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([CH:31]=[CH2:32])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 160 °C

Procedure:
cis-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.421 mmol, 150 mg) was dissolved in DME (1 ml) and ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml), tetrakis(triphenylphosphine)Pd(0) (0.021 mmol, 24.32 mg) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane-pyridine complex (0.631 mmol, 152 mg) were added and the reaction mixture was heated at 160° C. for 15 minutes in a microwave reactor. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were concentrated in vacuo and then purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford cis-2-benzyl-3a-methyl-6-vinyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (100 mg), m/z: 304.2 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([Pb+3])=[C:31]([CH2:38][CH3:39])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH2:38][CH3:39])[CH:30]=1
Reactant: CCc1cc(Br)cc(CC)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(CC)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 4.2 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (1 g, 6.5 mmol) and 4-dimethylamino-pyridine (3.96 g, 32.5 mmol) are added to a mixture of chloroform (20 ml) and toluene (5 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2,6-diethylphenyllead triacetate (4.25 g, 7.14 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2,6-diethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.1 g).
Reaction SMILES: CC(N(C)C)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH3:18][NH:19][CH2:20][CH2:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23].[H-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:18][NH:19][CH2:20][CH2:21][CH:22]([O:23][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:7]
Reactant: CNCCC(O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Product: Cl
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of dimethylacetamide (70 ml), toluene (20 ml), 4-chlorobenzotrifluoride (15 ml) and 3-methylamino-1-phenyl-1-propanol (15.6 ml) was heated to 115° C. A suspension of sodium hydride (6.2 g) in toluene (20 ml) was added gradually. The mixture was kept at 115° C. for 1 hour and cooled. Water (160 ml) and toluene (160 ml) were added. The phases were separated. The dried toluene phase was treated, with cooling, with gaseous hydrogen chloride. Fluoxetine hydrochloride (27.6 g) was precipitated. It was filtered and dried.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:3]([OH:9])[CH:4]([CH:6]1[CH2:8][CH2:7]1)[F:5].[C:17]([O:21][C:22]([N:24]1[CH:28]=[C:27]([CH2:29][C@H:30]([NH:34][C:35](=[O:52])[C@@H:36]([CH2:44][S:45]([C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](O)=[O:32])[N:26]=[CH:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C)C=O>[C:48]([S:45]([CH2:44][C@@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:35]([NH:34][C@@H:30]([CH2:29][C:27]1[N:26]=[CH:25][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH:28]=1)[C:31]([NH:1][C@@H:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:3]([OH:9])[C@H:4]([CH:6]1[CH2:8][CH2:7]1)[F:5])=[O:32])=[O:52])(=[O:47])=[O:46])([CH3:49])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Reactant: NC(CC1CCCCC1)C(O)C(F)C1CC1
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](F)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 147 mg (0.64 mmol) of (1S or R,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1-fluoro-2-butanol, 365 mg (0.7 mmol) of (S)-1-(tert-butoxycarbonyl)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 71 mg (0.7 mmol) of triethylamine, 114 mg (0.7 mmol) of HOOBT and 285 mg (0.7 mmol) of HOBTU in 15 ml of dimethylformamide is stirred at room temperature overnight under argon. Thereafter, the dimethylformamide is evaporated in a high vacuum and the residue is taken up in 50 ml of ethyl acetate. The ethyl acetate phase is washed with 20 ml of saturated sodium bicarbonate solution and 20 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-3-fluoro-2-hydroxypropyl]-1-Boc-imidazole-4-propionamide as a yellowish foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CN1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of 3.0 g (0.03 mole) of 3-hydroxy-1-methylpyrrolidine, 3.1 g (0.03 mole) of triethylamine, and 25 mL of methylene chloride was added 5.6 g (0.03 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to a residue. The residue was dissolved in ether, the solution filtered, and the filtrate concentrated to give 5.75 g of product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]([C:12]([OH:14])=O)=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>>[O:26]=[C:20]1[CH:19]([N:18]2[C:12](=[O:14])[C:6]3[C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:15]2=[O:17])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: COc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Reactant: NC1CCC(=O)NC1=O
Product: COc1cc(C(=O)O)c2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 5-methoxy-benzene-1,2,3-tricarboxylic acid with 3-aminopiperidine-2,6-dione, in one embodiment, in the presence of a coupling reagent, to form 2-(2,6-dioxo-piperidin-3-yl)-6-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carboxylic acid;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]#[N:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]#[N:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Br)cn2)CCC(=O)CC1
Reaction time: 22 h
Yield: 94.7 %

Procedure:
To 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (3.4 g) described in Reference Example 82 was added trifluoroacetic acid (4.1 ml) at room temperature, and stirred at the same temperature for 22 hours. After completion of the reaction, the solvent and trifluoroacetic acid were evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane:ethyl acetate) to give 1-(5-bromopyridin-2-yl)-4-oxocyclohexanecarbonitrile (2.78 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([C:20]([N:17]1[CH2:18][CH2:19][S:14][CH2:15][CH2:16]1)=[O:21])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N1CCSCC1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN(C)C(=O)N1CCSCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 111.5 %

Procedure:
N-t-Butoxycarbonyl-N,N'-dimethylethylenediamine (200 mg) was added to a solution of thiomorpholinocarbonyl chloride (228 mg) and triethylamine (123 mg) in methylene chloride (10 ml) which was cooled at 0° C. The mixture was stirred at ambient temperature for 20 minutes and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 0.6N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give N-t-butoxycarbonyl-N'-thiomorpholinocarbonyl-N,N'-dimethylethylenediamine (376 mg) as an oil. Rf: 0.43 (chloroform:methanol, 10:1, V/V)
Reaction SMILES: [Li+].[OH-:2].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]2[C:20](=[O:21])[CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[N:16]([CH3:26])[C:15]2=[O:27])[CH2:9][CH2:8]1)=[O:6]>O1CCOCC1.O>[C:15]([N:16]([CH3:26])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]([NH:14][CH2:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([OH:4])=[O:6])[CH2:8][CH2:9]1)=[O:21])([OH:27])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3N(C)C2=O)CC1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)O)c1ccccc1CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
LiOH (1.3 mmol, 0.03 g) was added to a solution of trans-4-(1-Methyl-2,4-dioxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexane carboxylic acid methyl ester (0.84 mmol, 0.29 g) in dioxane (3 mL) and water (3 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with DCM, then HCl (1N) was added until reached pH 1, then extract with DCM (3×10 mL) and AcOEt (3×10 mL). The organic layers were washed with brine (2×10 mL) dried over Na2SO4 collected together and concentrated under reduced pressure to give the title compound in quantitative yield (0.29 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:8]=[C:7]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:6]=1)=O.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[C:30]2[CH3:37].C[Al](C)C>C1(C)C=CC=CC=1>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([C:30]=1[CH3:37])=[CH:28][C:27]([NH:26][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:6]=1)=[O:2])=[CH:35][CH:34]=2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: COC(=O)c1cc(OCCN2CCOCC2)nc(N2CCOCC2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ccc(NC(=O)c3cc(OCCN4CCOCC4)nc(N4CCOCC4)n3)cc2c1C
Temperature: 25 °C

Procedure:
To a stirred mixture of compound (I) (1.02 g, 2.9 mmol) and 5-amino-2,3-dimethylindole (488 mg, 3.04 mmol) in toluene (6.9 mL) that was heated briefly until components partly dissolved and cooled to ambient temperature, was added 2 M solution of trimethylaluminum in toluene (2.32 mL, 1.6 eq) drop-wise under nitrogen purge. Reaction mixture was stirred until bubbling (gas evolution) completed, and then heated at 115° C. (oil bath) for 15 minutes. To a cooled reaction mixture chloroform and 1 N NaOH were added, chloroform layer was separated, washed twice with water, brine and dried over anhydrous sodium sulfate. Flash column chromatography on silica gel (eluent dichloromethane-acetone-methanol (3:1:01)) and recrystallization from chloroform-ethyl acetate mixture afforded target amide, 2-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (2,3-dimethyl-1H-indol-5-yl)-amide, as a pale yellow solid (1.1 g, 79%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=O)=[C:18]([CH:23]=3)[C:19](OC)=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1.Cl.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[OH:36].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:23]=[C:18]4[C:17]([CH2:24][N:29]([C@@H:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]5[OH:36])[C:19]4=[O:20])=[CH:16][C:15]=3[CH3:26])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1C=O
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-c3cn(C)nc3C)nc1)C(=O)N([C@@H]1CCCC[C@H]1O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A solution of methyl 5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-formyl-4-methylbenzoate (0.09 g), trans-2-aminocyclohexanol hydrochloride (0.04 g), triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.06 g) in THF (2.00 mL) was stirred at room temperature for 1.5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.00 mL) and THF (2.00 mL), sodium triacetoxyborohydride (0.11 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:28]3[C@H:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:28]3[C@H:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
N,N'-Carbonyldiimidazole (1 g) is added to a solution, cooled to +5° C., of 2-methoxyphenylacetic acid (1 g) in dry dichloromethane (30 cc). The mixture is stirred for 40 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (2 g) and triethylamine (1.7 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 1.8 cm, height 13 cm), eluting with ethyl acetate and collecting 25-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of acetonitrile (5 cc) and isopropyl ether (10 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aR,7aR)-(-)-7,7-Diphenyl-2-[(2-methoxyphenyl)acetyl]perhydro-4-isoindolone (1.7 g) is obtained in the form of white crystals, m.p. 200° C.; [α]D20 =-274° (c=0.49, acetic acid).
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH2:3][O:4][CH3:5].S(Cl)([Cl:14])(=O)=O>CCOCC>[F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH2:3][O:4][CH2:5][Cl:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCC(F)(F)C(F)(F)F
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)COCCl

Procedure:
The ether V can be prepared by a method analogous to that described by Weinmayr1, or from methyl 2,2,3,3,3-pentafluoropropyl ether and one molar equivalent of sulfuryl chloride at 0°-35°C with ultraviolet irradiation to give the chloromethyl 2,2,3,3,3-pentafluoropropyl ether XXVII,
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:5]=1[CH2:6][NH:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]([CH3:22])[C:9]1=[O:23].C(O)C.O1CCCC1>O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:10]([CH3:22])[C:9](=[O:23])[N:8]([NH:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:4]=3[Cl:3])[C:12]=2[CH:13]=1)([OH:19])=[O:18]
Reactant: CCOC(=O)c1ccc2c(c1)n(NCc1ccc(Cl)cc1Cl)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(NCc2ccc(Cl)cc2Cl)c2cc(C(=O)O)ccc21
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
Ten percent sodium hydroxide (0.650 g) was added to a mixture of 1-(2,4-dichlorobenzylamino)-6-(ethoxycarbonyl)-3-methyl-2-benzimidazolone (0.308 g), ethanol (4 ml), tetrahydrofuran (8 ml) and water (4 ml), and the mixture was stirred at 60° C. for 2.5 hr. A part of the reaction mixture was concentrated, and neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals precipitated were filtered and dried to give the objective compound (0.276 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH:15]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)C>[CH:15]1([N:22]2[C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[N:5]=[C:4]([CH3:11])[C:3]=3[CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCCC1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2ncnn2c2c1CCN2C1CCCCCC1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.98g of cycloheptylamine, 3 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1.5 hours and treated thereafter as described in Example 5. The crystals thus obtained were crystallized from tetrahydrofuranisopropyl ether to give 1.4g of pale yellow needles of m.p. 197° - 198° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:3][Cl:4].[Mg].[CH2:14]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])Cl)[CH3:15]>O1CCCC1>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:14][CH3:15])=[CH:8][CH:7]=1)[CH2:3][Cl:4]
Reactant: CC(CCl)Cc1ccc(Br)cc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Mg]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1ccc(CC(C)CCl)cc1

Procedure:
a solution of 24.7 parts of 2-methyl-3-(4-bromophenyl)-propyl chloride in 20 parts of tetrahydrofuran (THF) were added dropwise to 2.4 parts of magnesium in 25 parts of THF. The reaction was maintained at from 50° to 52° C., and the mixture was then refluxed for a further 30 minutes. 16.5 parts of triethylchlorosilane were added dropwise at room temperature and the mixture was then refluxed again for 6 hours, cooled and filtered. The solution was concentrated and the residue was distilled to give, at a boiling point of 115°-120° C./0.01 mm Hg, 20.3 parts of 2-methyl-3-(4-triethylsilylphenyl)-propyl chloride of n24 1.5080.