Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.[N:42]1([CH2:48][C:49]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[O:50])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:45]3[CH2:44][CH2:43][N:42]([CH2:48][C:49]([N:51]4[CH2:52][CH2:53][CH2:54][CH2:55]4)=[O:50])[CH2:47][CH2:46]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C40H48N6O5SCl2 [(M+H)+] 795.2857, observed 795.2851.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:43][O:44][C:45](=[O:60])[C:46]([CH3:59])([CH3:58])[CH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51]([CH:55]=O)=[C:50]([CH3:57])[CH:49]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:43][O:44][C:45](=[O:60])[C:46]([CH3:58])([CH3:59])[CH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[C:51](/[CH:55]=[CH:2]/[C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][C:11]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)=[N:12][N:13]=3)=[CH:5][C:4]=2[N+:21]([O-:23])=[O:22])=[C:50]([CH3:57])[CH:49]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Reactant: O=[N+]([O-])c1cc(-c2nnc(-c3ccc(Cl)cc3)o2)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(/C=C/c2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C

Procedure:
Combine 2-(4-bromomethyl-3-nitro-phenyl)-5-(4-chloro-phenyl)-[1,3,4]oxadiazole (894 mg, 2.27 mmol) and PPh3 (656 mg, 2.50 mmol) in DMF (13 mL) and heat to 95° C. under N2 for 4.5 h. Add 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (intermediate A in Example 1-62, 675 mg, 2.72 mmol) and K2CO3 (627 mg, 4.54 mmol), continue heating at 95° C. for 6.5 h. Allow the reaction to cool to room temperature. Dilute the cooled reaction with EtOAc (150 mL) and extract with water (50 mL). Dry the organic layer over Na2SO4 and evaporate the solvent. Purify the resulting oil by silica gel chromatography (10-45% EtOAc/HEP) to afford a yellow solid: (M+H)+ 546.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.O.OC1C2N=NNC=2C=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][CH2:30][C:31](O)=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:31](=[O:32])[CH2:30][CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:6]2
Reactant: O=C(O)CCc1cccs1
Reactant: COc1ccc2c(c1)CCNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6-methoxyisoquinoline (3.29 g), hydroxybenzotriazole monohydrate (5.72 g) and 3-(2-thienyl)propanoic acid (3.31 g) in 280 ml of dry tetrahydrofuran (THF) at 0° C. was added DCC (4.37 g) in one portion. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was filtered and concentrated. The residue was taken up into 200 ml of ethyl acetate (EtOAc) refiltered, washed with 5% aq. HCl (50 ml), 5% aq. NaCl (50 ml), 10% aq. KOH (50 ml), dried (MgSO4), filtered, and concentrated. Chromatography on silica gel (elution with 20% EtOAc:hexanes) afforded 4.54 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=C1OCCO1
Reactant: Oc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc2cnccc12
Temperature: 155 °C
Yield: 67.5 %

Procedure:
A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylene carbonate (1.43 g, 16.2 mmol), K2CO3 (0.97 g, 7.1 mmol) in DMF (6 mL) was heated at 155° C. for 1.5 h under stirring in a sealed tube. After cooling, the mixture was diluted with CHCl13 and filtered through a pad of Celite. The brownish filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel using EtOAc as eluent to give 1.8 g (67%) of the title product as a beige oil which solidified on standing: mp 64-67° C.; HRMS m/z calcd for C11H11NO2 (M)+ 189.0790, found 189.0789. Anal. (C11H11NO2) C, H, N.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17]I)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1.S(=O)(O)[O-].[Na+].O>O1CCOCC1>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CI)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A solution of 1.8 g of 9-fluoro-21-iodo-11β-hydroxypregna-1,4,16-triene-3,20-dione in 135 ml of dioxane is stirred with 90 ml of 5% sodium bisulfite at 105°C under nitrogen for 1.5 hours. The solution is cooled, poured into water, stirred for 30 minutes and filtered. The solid is washed with water and dried in a vacuum oven at 60°C over phosphorous pentoxide to give 780 mg of material. Crystallization from chloroform-methanol gives 420 mg of the title compound, melting point 327°-328°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: CC(C)CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.5 g, 2 7 mmol) was dissolved in methanol (25 mL). Isovaleraldehyde (0.233 g, 2 7 mmol) was added followed by acetic acid (1 mL). The solution continued to stir at 25° C. for 10 min. Sodium cyanoborohydride (0.424 g, 6.75 mmol) was added and the mixture was stirred at 25° C. for 5 h. The mixture was poured into aqueous half-saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-(3-methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.43 g, 1.7 mmol, 63%), as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C15H27NO2 253.2, found 254.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.O=[C:26]1[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27]1.O>C1(C)C=CC=CC=1>[C:31]([CH:28]1[CH2:29][CH2:30][C:26]2([O:6][CH2:5][C:2]([CH3:7])([CH3:1])[CH2:3][O:4]2)[CH2:27]1)([OH:33])=[O:32]
Reactant: COC(=O)C1CCC(=O)C1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCC(C(=O)O)C2)OC1

Procedure:
72.8 g (0.70 mole) of 2,2-dimethylpropane-1,3-diol and 12.2 g (0.05 mole) of pyridinium-4-toluenesulphonate are added one after another to 40.0 g (0.28 mole) of methyl 3-oxocyclopentane carboxylate OCCME in 560 ml of absolute toluene. The mixture is boiled for 1.5 hours in a water separator; after 30 minutes the solid is dissolved. Approximately 8 ml of H2O in total are separated out. After cooling, the solution is washed three times using 100 ml of H2O each time, the toluene phase is dried over MgSO4 and evaporated in vacuo. The oily residue is fractionally distilled in vacuo at 0.6 mbar over a metallised pin tube column 20 cm long.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24](=[O:25])[NH:23][C:22](=[O:26])[NH:21]2)[C:13]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC>[CH2:5]([O:4][C:2]([N:21]1[C:14]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]([CH2:11][C:10]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:8]([Cl:7])[CH:9]=3)[C:13]2=[O:27])[C:24](=[O:25])[NH:23][C:22]1=[O:26])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)N1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A solution of ethyl chloroformate (0.55 g.) in 1,2-dimethoxyethane (20 ml.) was added dropwise to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) and sodium carbonate (2.0 g.) in 1,2-dimethoxyethane (60 ml.). When the addition was completed, the mixture was stirred for 16 hours and then evaporated. The residual solid was dissolved in warm water (150 ml.) and the solution obtained was slowly acidified (concentrated hydrochloric acid). The solid which was precipitated was separated by filtration, washed with water, air-dried and recrystallised twice from propan-2-ol/petrol 60-80 to give 3-ethoxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.35 g.), m.p. 192°-194° C.
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14]1([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]4[CH2:1][CH2:2][CH2:3][C@@H:4]4[CH2:13]3)=[O:30])=[CH:32][CH:33]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)NC[C@H]1CCCN21
Product: O=C(Nc1ccc(C(=O)N2C[C@H]3CCCN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 57.8 %

Procedure:
The same procedures used in Example 1 were repeated using (3aR)-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 15 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound after recrystallization from dioxane-hexane. Yield 57.8%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25][C:26](O)=[O:27])=[CH:23][CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:20]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:26](=[O:27])[CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C), 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[4-({2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:13]([OH:15])=O.[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8][CH2:7]2)=[O:15])[CH:20]=[N:19]1)[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCO2
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCOc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 60.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxychroman-4-carboxylic acid (0.31 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide (0.39 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:17]([F:21])([F:20])(Br)Br>C1COCC1.CCOCC.[Zn]>[C:1]([O:5][C:6](=[O:16])[N:7]([CH:8]1[CH2:13][CH2:12][C:11](=[C:17]([F:21])[F:20])[CH2:10][CH2:9]1)[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Reactant: FC(F)(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)C1CCC(=C(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (0.69 g, 3.04 mmol, 1.0 eq.) in THF (25 mL) at −30° C. was added CBr2F2 (1.25 mL, 4.5 eq.) followed slow addition of by P(N(CH3)2)3. The resulting mixture was warmed to room temperature over 0.5 h and Zn was introduced. The resulting mixture was stirred at reflux for 16 h, cooled to room temperature and diluted with Et2O. The organic phase was decanted and the aqueous phase extracted with 2×Et2O. The combined organic phase was washed with saturated CuSO4 solution until it stayed blue, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (20% EtOAc-Hexanes) to give (4-difluoromethylene-cyclohexyl)-methyl-carbamic acid tert-butyl ester (475 mg, 60%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:14](/[N+:11]([O-:13])=[O:12])\[CH3:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: C/C(=C\c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 90 °C
Yield: 54.7 %

Procedure:
In a sulfonation flask 2,4-dichloro-benzaldehyde (77 g, 0.44 mol), nitroethane (216 ml, 3.04 mol) and ammonium acetate (81.4 g, 1.06 mol) were added to glacial acetic acid (600 ml). The resulting solution was heated to 90° C. for three hours. After removal of the solvent ice-water (400 ml) was added. The solid product was collected by filtration, washed with water and recrystallized from ethanol. 55.9 g (55% of theory) of 2,4-dichloro-1-((E)-2-nitro-propenyl)-benzene was obtained in the form of a yellow solid (m.p. 79-81° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][Si:5]1(C2C=CC=CC=2)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])=[CH:27][F:28])=[CH:22][CH:21]=1>>[CH3:18][CH:2]([CH3:1])[CH2:3][CH2:4][Si@H:5]1[CH2:6][CH2:7][C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])=[CH:27][F:28])=[CH:22][CH:21]=3)=[CH:22][CH:21]=2)[CH2:9][CH2:10]1
Reactant: FC=C(F)c1ccc(Br)cc1
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(=O)CC1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(C(F)=CF)cc3)cc2)CC1

Procedure:
The general procedure of Example 35 was repeated using 4-(3-methylbutyl)-4-phenyl-4-silacyclohexanone instead of 4-pentyl-4-phenyl-4-silacyclohexanone and 4-bromo-1-(1,2-difluorovinyl)benzene instead of 4-bromo-2,6-difluoro-1-(2,2-difluorovinyloxy)benzene, thereby obtaining the intended compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:13])[C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH3:37])[C:21]1=[O:38])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([C:9](=[O:13])[C:10]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH3:37])[C:21]2=[O:38])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)C(=O)c1cc(F)cc(F)c1
Product: C[C@H](NC(=O)C(=O)c1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluoro-α-oxoacetic acid (Example O) and 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a solid (mp.=128-129° C.). The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (30:70).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:15])=[O:14])[CH2:9]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:15])=[O:14])[CH2:9]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)C1
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: CC#N
Product: COc1ccc(-c2cncc(Cl)c2N2CCC(C(N)=O)C2)cc1

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carboxamide E21 (23 mg, 0.088 mmol), 4-methoxybenzene boronic acid (13 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to give impure title compound as a white solid (15 mg). Further purification by preparative hplc (H2O, MeCN, gradient 90:10 to 10:90 over 30 min) furnished the title compound as a white solid, LC-MS (ESI, 3.5 min) Rt 1.40 min, m/z 332 (100%, [M+H]+); m/z (ESI, 3.5 min) C17H18ClN3NaO2 requires 354.0980 found [M+Na]+ 354.0980
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[NH:19]CCO.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[NH2:19][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:13])[CH2:6]2
Reactant: CC1(C2CCCC2)Cc2cc(NCCO)c(Cl)c(Cl)c2C1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(N)c(Cl)c(Cl)c2C1=O
Reaction time: 8 h

Procedure:
A stirred solution of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-(2-hydroxyethylamino)-2-methyl-1H-inden-1-one (2.0 g) in acetone (50 ml) is treated with Jones Reagent (3 ml) at 25° C. over a 1 hour period. The reaction mixture is allowed to stand overnight then filtered free of chromium salts. The acetone is evaporated in vacuo and the 5-amino-6,7-dichloro-2-cyclopentyl-2,3-dihydro-2- methyl-1H-inden-1-one thus obtained (800 mg) is used in Step D without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:17]([N:20]([CH:25]([CH3:27])[CH3:26])[C:21](=[O:24])[CH2:22]Br)([CH3:19])[CH3:18]>>[CH:17]([N:20]([CH:25]([CH3:27])[CH3:26])[C:21](=[O:24])[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N(C(=O)CBr)C(C)C
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Product: CC(C)N(C(=O)COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Yield: 84.5 %

Procedure:
The product was prepared as in Example 2, Stage A starting with 900 mg of 4'-hydroxy-(4-nitro biphenyl) (Aldrich) and 958 mg of N,N-bis-(isopropyl)-2-bromo-acetamide (Preparation 8) to obtain 1.26 g of the expected product.
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1)[CH:2]=C.[O:18]=[O+][O-]>ClCCl>[O:18]=[CH:2][CH2:1][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCCC2)O1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-propenyl)-1,5-dioxa-spiro[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 5.6 g (21.36 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 4.04 g of pure (±)-cis-4-(2-oxo-ethyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:11]=[CH:10]2
Reactant: N[C@@H]1CCc2ccccc21
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: Clc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 125 °C
Yield: 33.9 %

Procedure:
A stirred mixture of 2,6-dichloro-quinoline (4.8 g, 24 mmol) and (R)-1-aminoindane (6.5 g, 48 mmol) was heated in a sealed tube for 16 h at 125° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane) yielded (6-chloro-quinolin-2-yl)-(R)-indan-1-yl-amine as a yellow solid (2.4 g, 34%), MS 295.1 [(M+H)+].