Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1([CH3:38])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[CH2:20][N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([O:24][CH:25]([CH:27]3[CH2:29][CH2:28]3)[CH3:26])=[O:23])[C@H:5]2[S:4]1.C(=O)(O)[O-].[Na+].[CH3:44][C:45]1[S:49][C:48]([SH:50])=[N:47][N:46]=1.O>C(N)=O>[CH3:44][C:45]1[S:49][C:48]([S:50][CH2:2][C:3]2([CH3:38])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[CH2:20][N:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:22]([O:24][CH:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])=[O:23])[C@H:5]3[S:4]2)=[N:47][N:46]=1
Reactant: Cc1nnc(S)s1
Reactant: CC(OC(=O)N(CC(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CBr)S[C@H]12)c1ccccc1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: NC=O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)CN(C(=O)OC(C)C4CC4)c4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Reaction time: 4.5 h
Yield: 10.8 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (3.6 g) in formamide (40 ml) was added to a solution of sodium bicarbonate (0.66 g) and 5-methyl-1,3,4-thiadiazole-2-thiol (1.1 g) in formamide (60 ml) under ice-cooling, after which the mixture was stirred for 4.5 hours at the same temperature. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate aqueous solution and then with water, dried, after which the solvent was distilled off. The oily residue was subjected to column chromatography on silica gel (110 g) and eluted with chloroform. The eluate was separated into fractions of each 50 ml and after collecting the fractions of the fifteenth and sixteenth, the solvent was distilled off to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (0.42 g).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH2:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1COCC1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C(N(CC)CC)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH:29][C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1

Procedure:
To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol), THF (5 mL), and dimethylcarbamyl chloride (50 mg) is added triethylamine (50 mg). After 10 min the solution is partitioned between EtOAc and water. The organic layer is separated and washed further with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C)C=O>[Br:1][C:2]([Br:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6]([Cl:15])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(CC=C(Br)Br)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)C(CC=C(Br)Br)C(=O)Cl
Yield: 59 %

Procedure:
In 20 g of benzene were dissolved 2.0 g of α-(3,3-dibromoallyl) isovaleric acid, followed by the addition of 4.7 g of thionyl chloride and 2 drops of N,N-dimethylformamide. The mixture was refluxed overnight and, then, distilled to remove the low-boiling fraction. As the residue there was obtained α-(3,3-dibromoallyl)isovaleroyl chloride. This α-(3,3-dibromoallyl) isovaleroyl chloride was dissolved in 30 g of dry benzene and 1.5 g of α-ethynyl-3-phenoxybenzyl alcohol were added. This was further followed by the dropwise addition of 1.6 g of pyridine and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was further stirred at 40°-50° C. for 2 hours, after which it was diluted with diethyl ether, washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The resultant viscous oil was purified by column chromatography to recover 2.0 g of α-ethynyl-3-phenoxybenzyl α-(3,3-dibromoallyl)isovalerate (Compound [10]) which was shown to have the properties indicated below [yield: 59% based on α-(3,3-dibromoallyl)isovaleric acid].
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[C:20]([F:27])[C:19]=3[CH:28]([F:30])[F:29])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>[C].[Pd]>[F:30][CH:28]([F:29])[C:19]1[C:20]([F:27])=[C:21]([O:24][CH2:25][CH3:26])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH:7]2[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12]1
Reactant: CCCC1CCC(C2CCC(C=Cc3ccc(OCC)c(F)c3C(F)F)CC2)CC1
Agent: [Pd]
Product: CCCC1CCC(C2CCC(CCc3ccc(OCC)c(F)c3C(F)F)CC2)CC1
Reaction time: 48 h

Procedure:
1.6 g of β-(4-(4-propylcyclohexyl)cyclohexyl)-2-difluoromethyl-3-fluoro-4-ethoxy styrene obtained in Example 5 was dissolved in 25 ml of a mixed toluene-solmix solvent. A palladium carbon catalyst was added to the solution in a nitrogen atmosphere and a hydrogenation reaction was conducted at ambient temperature and pressure for 2 days. After the completion of the reaction, the catalyst was removed by filtration. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluent: heptane/toluene=9/1) to obtain 1-(2-difluoromethyl-3-fluoro-4-ethoxyphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane. This was further recrystallized twice from a heptane/ethanol mixed solvent to obtain pure 1-2-difluoromethyl-3-fluoro-4-ethoxyphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane. The compound showed a liquid crystal phase and the transition point was as described below.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C@@H:7]([CH2:10][C:11](OCC)=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19]>CO.CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C@@H:7]([CH2:10][C:11]([NH:19][CH3:18])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(F)ccc2N1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNC(=O)C[C@H]1COc2cc(F)ccc2N1
Temperature: 20 °C
Yield: 99.2 %

Procedure:
Ethyl [(3S)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 10a, 50.0 g, 204.2 mmol) was dissolved in MeOH (150 mL) in a 500 mL jacketed vessel at 20° C. Methylamine (127 mL of a 33% w/w solution in EtOH, 96 g, 1.02 mol) was added in one portion and the mixture stirred at 20° C. over night. The solution was sampled and found not to have reached completion by HPLC analysis. The reaction was left stirring for a further 2 h then additional methylamine in EtOH (25.0 mL of a 33% w/w solution in EtOH; 18.9 g; 200.8 mmol) was added and the solution stirred over night at 20° C. The solution was evaporated in vacuo to an orange oil, then MeOH (300 mL) added and the mixture re-evaporated giving a beige solid, that was ground up using a mortar and pestle, then dried in a vacuum oven at 40° C. for 3 h to yield the title compound (46.3 g, 99.2% yield NMR assay 98.1% w/w, 99.7% e.p. by chiral HPLC %).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[NH:15][C:14](=[O:16])[C:13]3([CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17]3)[N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[N:15]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:14](=[O:16])[C:13]3([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22]3)[N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)NC(=O)C12COCCOC2
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1cccc(F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
28 mg (0.66 mmol) sodium hydride were added to 0.21 g (0.55 mmol) tert-butyl 3-(3-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 20 ml DMF. After 20 min at RT 63 μl (0.65 mmol) methyl bromoacetate were added dropwise at 0° C. Then the mixture was stirred for 30 min in the ice bath and then for 5 h at RT. The reaction mixture was poured onto water poured and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31](=[O:41])[C@@H:32]([NH2:40])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:12][N:11]([CH3:42])[N:10]=1.C(N(CC)CC)C.[CH:50]1([CH2:55][C:56](O)=[O:57])[CH2:54][CH2:53][CH2:52][CH2:51]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O.[OH-].[Li+].C(O)(=O)C>ClCCl.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31](=[O:41])[C@@H:32]([NH:40][C:56](=[O:57])[CH2:55][CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)[CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:24])=[CH:20][CH:21]=2)=[CH:12][N:11]([CH3:42])[N:10]=1
Reactant: O=C(O)CC1CCCC1
Reactant: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)[C@@H](N)Cc3ccccc3)cc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)[C@H](Cc3ccccc3)NC(=O)CC3CCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To a solution of compound 19 (6.5 g, 11.57 mmol) in dry dichloromethane (100 mL) was added triethylamine (9.68 mL, 69.42 mmol) and cyclopentylacetic acid (4.35 mL, 34.71 mmol). The resultant solution was stirred at rt for 5 min. (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 15.36 g, 34.71 mmol) was added into the above solution in portions. The final mixture was stirred at rt overnight. The solvent was removed with rotavapor. To the residua was added THF (60 mL) and methanol (60 mL). A suspension of lithium hydroxide monohydrate (5.0 g, 119.2 mmol) in water (30 mL) was slowly added to the above solution. The mixture was stirred at rt for 1.5 hours and then neutralized with acetic acid (7.0 mL, 122.3 mmol). The mixture was diluted with ethyl acetate (˜300 mL), and washed with brine, and dried over sodium sulfate. It was filtered, concentrated and purified with silica column chromatography eluting with dichloromethane-ethyl acetate (v/v 9/1). After crystallizing with hexanes/ethyl acetate, the title compound (20, 5.1 g) was obtained as white solid in 65.6% yield.
Reaction SMILES: [O:1]1[CH:7]=[CH:6][CH:5]=[N:4][C:3](=[O:8])[CH2:2]1.F[B-](F)(F)F.[CH3:14][O+](C)C>C(Cl)Cl>[CH3:14][O:8][C:3]1[CH2:2][O:1][CH2:7][CH2:6][CH2:5][N:4]=1
Reactant: C[O+](C)C
Reactant: O=C1COC=CC=N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCCOC1
Reaction time: 4 h
Yield: 79.1 %

Procedure:
The product from step 4 (1.06 g, 9.2 mmol) was dissolved in 11 mL of DCM and the stirred solution was treated with trimethyloxonium tetrafluoroborate (1.70 g, 11.5 mmol) and the mixture was stirred for 4 hours. The reaction was quenched by addition of 1.70 mL saturated aqueous K2CO3 and the mixture was vigorously stirred for 15 minutes. The precipitate was removed by filtration and the filtrate concentrated in vacuo to provide 3-methoxy-2,5,6,7-tetrahydro-1,4-oxazepine (0.94 g, 80%) as a clear oil that was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].Cl>CN(C=O)C>[CH3:27][O:26][C:24]([C:23]1[CH:22]=[C:21]([CH2:20][N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]2=[O:18])[CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (4.76 g, 20 mmol) in 50 mL DMF was added to a suspension of Nail (0.8 g, 20 mmol) in 25 mL DMF. The suspension was stirred at ambient temperatures for 30 minutes, then heated to 50° C. for 30 minutes. A solution of methyl 3-bromomethylbenzoate (2.86 g, 12.5 mmol) in 20 mL DMF was then added and the reaction stirred for 10 min at 50° C. The mixture was poured into 1 N HCl, filtered, washed with water and dried. Chromatography on silica gel (2% EtOH in 7:3 methylene chloride/ethyl acetate) afforded 1.2 g of 3-(3-methoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:16]([OH:17])[CH:15]([Cl:18])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1>FC(F)(F)C(O)=O>[ClH:18].[NH2:2][CH:3]1[C:16](=[O:17])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: NC1Cc2ccc3ccccc3c2C(Cl)C1O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccc3ccccc3c2CC1=O
Yield: 48.8 %

Procedure:
2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride (40 mg) was refluxed in trifluoroacetic acid (17 ml) for 31/2 hours. The solvent was removed in vacuo and the residue was crystallized from a cyclohexane/ethyl acetate mixture to yield the title compound (17 mg) as a cream-colored powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC1C=CC(S(O[CH2:18][C@@H:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][N:20]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])(=O)=O)=CC=1.[OH-].[Na+]>C(OC)(C)(C)C>[CH3:18][C@@H:19]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3ccccc3CN2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2C)cc1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 8.15 g (214.8 mmol) of lithium aluminium hydride (LiAlH4) in 800 mL of methyl tert-butyl ether (MTBE) there are added 101.2 g of the ditosyl compound obtained in Step A (214.8 mmol) dissolved in 200 mL of MTBE. The batch is then heated at 50° C. for 2 hours. It is allowed to cool and placed at 0° C., and there are then added, dropwise, 12 mL of 5N NaOH solution. The batch is stirred at ambient temperature for 45 minutes. The solid thereby obtained is then filtered off and washed with MTBE and then with dichloromethane. The filtrate is then concentrated to dryness. The title product is then obtained in the form of a solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Br:8][C:6]1[N:7]=[C:2]2[N:25]([CH2:24][C@H:21]3[CH2:22][CH2:23][C@H:18]([O:17][CH3:16])[CH2:19][CH2:20]3)[C:11](=[O:13])[CH2:10][NH:9][C:3]2=[N:4][CH:5]=1
Reactant: CO[C@H]1CC[C@H](CN)CC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(Br)nc32)CC1
Temperature: 150 °C

Procedure:
A solution of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (500 mg, 1.47 mmol), ((trans)-4-methoxycyclohexyl)methanamine (317 mg, 2.21 mmol) and diisopropylethyl amine (0.77 mL, 4.42 mmol) in anhydrous dimethylsulfoxide (8.0 mL) was placed in a microwave vessel (20 mL). The reaction was heated to 150° C. for 1 h. The reaction was poured into water, extracted with ethyl acetate (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dissolved in acetic acid (30 mL) and placed in a sealed tube. The reaction was heated to 120° C. overnight. The solution was cooled, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate (3×100 mL), dried over sodium sulfate, filtered and adsorbed onto silica gel. Purification by flash chromatography (50% ethyl acetate in hexanes) gave a light orange solid (400 mg, 1.12 mmol, 76% yield). MS (ESI) m/z 355.2 [M+]+, 357.2 {M+2]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].N1C=CC=CC=1>O1CCOCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1
Temperature: 0 °C

Procedure:
2.68 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 3.14 g (20 mmol) of piperidine-4-carboxylic acid ethyl ester and 0.81 ml (10 mmol) of pyridine in 50 ml of dioxane for 5 hours. The reaction mixture is then poured out on 200 ml of ice water and suction filtered to separate the solid, and the filter cake is then washed with water.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4](Cl)[N:3]=1.CC(C)([O-])C.[K+].[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1c(N)nc(OCc2ccccn2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
102 mg (0.4 mmol) of 2-amino-6-chloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] and 54 mg (0.48 mmol) of potassium tert-butoxide are dissolved together in 1.696 g (=1.5 ml, 15.55 mmol) of 2-hydroxymethylpyridine, and the mixture is stirred at 60° C. for about 16 h. The product which crystallizes out is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:32]=[C:33]([O:44][CH2:45][CH2:46][O:47][C:48](=[O:56])[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[C:34]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])[C:18]([NH:20][CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:32]=[C:33]([O:44][CH2:45][CH2:46][O:47][C:48](=[O:56])[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[C:34]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc(C(=O)NCC(=O)OCc2ccccc2)cc1OCCOC(=O)Nc1ccccn1
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc(C(=O)NCC(=O)O)cc1OCCOC(=O)Nc1ccccn1

Procedure:
By hydrogenating benzyl {3-(4-tert-butyl-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyl-oxy)-ethoxy]-benzoylamino}-acetate, described in Example 18, in methanol over palladium/charcoal at RT and under normal pressure there was obtained {3-(4-tert-butyl-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyl-oxy)-ethoxy]-benzoylamino}-acetic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N>>[N:1]1[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[C:8]=2[CH:3]=[C:4]2[C:9]=3[CH:8]=[CH:7][CH:6]=[CH:5]2)=[CH:3][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Agent: N
Product: C1=Nc2c3c(ccc2=C1)=c1ccccc1=C3

Procedure:
In step two, the aryl hydrazone cyclizes in the presence of an acidic catalyst in a Fischer indole reaction with elimination of ammonia to give an indenoindole ligand precursor. The reaction apparently involves an interesting [3,3]sigmatropic rearrangement (see J. March, Advanced Organic Chemistry, 2nd ed. (1977) 1054). A variety of acidic catalysts are suitable, including, for example, Lewis acids (zinc chloride, boron trifluoride), and protic acids (hydrochloric acid, acetic acid, p-toluenesulfonic acid). Usually, the crude aryl hydrazone is simply heated with the acidic catalyst for a brief period to cause the cyclization reaction. The reaction product is isolated and purified by any suitable method. In one method, the cyclization reaction mixture is poured into ice water and extracted into an organic solvent. The solution is dried, filtered, and evaporated to give the crude indenoindole ligand precursor, which can be further purified by recrystallization. In contrast to the previous step, it is preferred to purify this reaction product prior to using it in the next step.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:6]([OH:8])=[O:7])C.[OH-].[Na+]>C(O)C>[CH2:19]([O:18][C:16]([NH:15][C:5]([CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])([C:6]([OH:8])=[O:7])[C:4]([OH:26])=[O:3])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)CC(NC(=O)OCc1ccccc1)(C(=O)O)C(=O)O

Procedure:
2-Benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid monoethyl ester was heated at 75° C. in ethanol (5 mL) with sodium hydroxide (5 mL, 1 N) for 3 h and 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid was isolated by extraction of the acidified reaction mixture. 2-Benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid was heated at 103° C. for 1 h and the resulting residue was purified by column chromatography on silica gel to give 2(RS)-benzyloxycarbonylamino-4-ethylhexanoic acid (0.220 g).
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1)=[O:39]
Reactant: CCOC(=O)CC1CCCNC1
Reactant: O=C(Cl)Cc1cccs1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Product: CCOC(=O)CC1CCCN(C(=O)Cc2cccs2)C1
Yield: 51.3 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 3-piperidinylacetate (414.2 mg; 2.4 mmol) and 2-thiopheneacetyl chloride (295 μl; 2.4 mmol). The crude product was purified by chromatography on silica, eluting with 50% ethyl acetate in hexane, giving ethyl 1-(2-thiopheneacetyl)-3-piperidinylacetate (364 mg) as a pale yellow oil. MS m/z (positive ion) 318 (M+Na+; 40), 296 (MH+; 100).