Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]C=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[N:22]1C=CC=C2CCC(N)C=12>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3=[N:22][CH:18]=[CH:17][CH:16]=[C:15]3[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCc2cccnc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCc3cccnc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 8.46, 7.60, 7.17, 5.37, 5.25, 3.11-2.95, 2.75-2.61, 1.94-1.81, 1.36-1.26; (MS/CI) calcd for C16H20N4+H 269.4, found 269.3.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[O:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)o1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)o1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-furancarboxylate (0.70 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylate as colorless crystals (0.41 g, yield 46%) from a fraction eluted with acetate-hexane (9:1, v/v). Recrystallization from ethyl ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][CH:10]1[C:14](=[O:15])[CH:13]=[C:12]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:11]1)=[N+]=[N-].[H][H].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CO.C(OCC)(=O)C.[Pd]>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH2:4][CH2:5][C:6]2[CH:23]=[CH:22][CH:21]=[C:8]([CH2:9][CH:10]3[CH2:11][C:12]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][C:14]3=[O:15])[CH:7]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: [H][H]
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCN=[N+]=[N-])c2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)COC1=CC(=O)C(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A mixture of 31 (0.059 g, 0.19 mmol) and Pd on C (10 wt %, 0.006 g) in methanol (3 mL) is stirred at rt for 1 h under 1 atmosphere of hydrogen. The reaction mixture was filtered to remove the catalyst. Water (0.5 mL) and 2 N sodium hydroxide (0.27 mL) were added and the reaction mixture was cooled to 0° C. in an ice-water bath. Then 4-chlorophenylsulfonyl chloride (0.082 g, 0.39 mmol) was added and the reaction mixture was stirred at 0° C. for 4 h and then diluted with ethyl acetate. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue so obtained was purified by silica gel column chromatography, using ethyl acetate-hexanes 1:1 as eluent, to provide the desired compound. Yield: 22%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:35][C:36]1[S:37][C:38]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:39]=2[N:40]=1>>[F:45][C:43]1[CH:42]=[CH:41][C:39]2[N:40]=[C:36]([NH:35][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[S:37][C:38]=2[CH:44]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: O=C(O)c1cccnc1Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(F)cc2s1)c1cccnc1Nc1ccc(Cl)cc1Cl
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and 2,4-dichloro aniline (18, 92 mg, 1 mmol) was taken in ethylene glycol and refluxed at 160° C. for 5 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain Ethyl. 2-(2,4-dichloro anilino) nicotinate (25) as pure product. Ethyl 2-(2,4-dichloro anilino) nicotinate (25, 311 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(2,4-dichlorophenylamino)nicotinic acid (32). To a stirred solution of 2-(2,4-dichlorophenylamino)nicotinic acid (32, 283 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-fluoro benzothiazole (36, 117 mg, 0.7 mmol) were added Then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (10) was purified by column chromatography employing EtOAc/hexane as an eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH2:14][CH3:15])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C.C(O)(=O)C.O>[CH2:1]([O:3][C:4]1[C:5]([CH2:14][CH3:15])=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(NC(C)=O)cc1CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])c(NC(C)=O)cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(4-Ethoxy-3-ethyl-phenyl) acetamide [3.1 g, Reference Example 33(e)] was dissolved in acetic anhydride (5 mL), a solution of nitric acid in acetic acid (0.5 mL of 95% nitric acid, in 4 mL) was added and the mixture was stirred overnight at ambient temperature. The mixture was diluted with water (100 mL) and the aqueous mixture was extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane/ethyl acetate 9/1) to give N-(4-ethoxy-5-ethyl-2-nitrophenyl)acetamide (3.0 g) as a bright yellow solid. LC-MS (Method E): RT=3.27 minutes, 253 (M+H)+. (h) 1-Ethoxy-2-ethyl-4-nitrobenzene
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([CH:42]=[CH2:43])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39](/[CH:42]=[CH:43]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]3(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC(C)(C)OC(=O)N1CCC(/C=C/c2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)C1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester analogous to Example 62, step B.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].N1CCCCC1>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](/[C:11]#[N:12])=[CH:19]\[C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N#CCc1nc2ccccc2s1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#C/C(=C/c1ccc(C#N)cc1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzothiazole-2-acetonitrile (750 mg, 4.3 mmol) and 4-cyanobenzaldehyde (564 mg, 4.3 mmol) are dissolved in ethanol (20 ml). Piperidine (11 mg, 0.13 mmol) is added, and the reaction is stirred at room temperature for 2 hours. A precipitate is formed, which is filtered and washed with additional ethanol (5 ml). The solid is dried in a vacuum desiccator overnight and used without further purification.
Reaction SMILES: C(#N)C.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([NH:19][C:7]1[C:8]([F:12])=[C:9]([F:11])[N:10]=[C:5]([F:4])[C:6]=1[F:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)Nc1c(F)c(F)nc(F)c1F
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To 100 ml of acetonitrile was added 24.5 g of pentafluoropyridine, and the mixture was stirred in an ice bath simultaneously with the dropwise addition of 30 g of t-butylamine. When the mixture warmed to room temperature, 150 ml of chloroform was added, and the mixture was washed twice with 800 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 23 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[O:18])[NH:16][N:15]=[N:14]1)([CH3:3])[CH3:2].[CH:19](I)([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH:19]([CH3:21])[CH3:20])[N:15]=[N:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: CC(C)c1cccc(C(C)C)c1-n1nn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1-n1nnn(C(C)C)c1=O
Reaction time: 2 h
Yield: 52 %

Procedure:
14.3 g of 1-(2,6-diisopropylphenyl)-5-oxo-2-tetrazoline, 12.8 g of isopropyl iodide and 10.4 g of pulverised potassium carbonate are dissolved in 140 ml of dimethylformamide and stirred for 2 hours at +60° C. The resulting suspension is poured onto water and extracted three times with ether. The combined ethereal phases are washed with water and saturated sodium chloride solution, dried over Na2SO4 and concentrated by evaporation. In order to remove the 1-(2,6-diisopropylphenyl)-5-isopropoxy-tetrazole formed as by-product, the mixture is chromatographed on silica gel with the eluant CH2Cl2 /cyclohexane (3:1). In this manner 8.7 g of 1-(2,6-diisopropylphenyl)-4-isopropyl-5-oxo-2-tetrazoline having a melting point of 60°-62° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2-c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2-c2cccs2)cc1
Yield: 97.5 %

Procedure:
A solution of 123 mg (0.492 mmol) of 4-methyl-2'-(2-thienyl)-1,1'-biphenyl, 18.5 mg of AIBN and 110 mg (0.62 mmol) of N-bromosuccinimide in 50 mL of carbon tetrachloride was heated at reflux until a negative starch iodide reaction was obtained (2 hr). The reaction mixture was evaporated under vacuum and the residue triturated with hexane. The hexane washes were filtered and the filtrate evaporated under vacuum to give 158 mg of product. 1H NMR (300 MHz, CDCl3): 4.48 (s, 2H), 6.68 (dd, 1H), 6.88 (dd, 1H), 7.11 (m, 5H), 7.36 (m, 3H), 7.50 (dd, 1H).
Reaction SMILES: [C:1](/[C:3](/[CH:13]=[CH2:14])=[CH:4]\[C@@H:5]1[C@@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2].S(Cl)([Cl:17])=O>O1CCCC1.CN(C)C=O>[C:1](/[C:3](/[CH:13]=[CH2:14])=[CH:4]\[C@@H:5]1[C@@H:7]([C:8]([Cl:17])=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C/C(C#N)=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
(1R)-trans-3-[(1Z)-2-cyano-1,3-butadienyl]-2,2-dimethylcyclopropanecarboxylic acid (440 mg, 2.30 mmol) was dissolved in 3 mL of tetrahydrofuran and then thionyl chloride (301 mg, 2.53 mmol) and 10 mg of N,N-dimethylformamide were added and the solution was stirred at room temperature for 1 hours, and further at 60° C. of 3 hours. The reaction solution was concentrated under reduced pressure condition to obtain 460 mg of (1R)-trans-3-[(1Z)-2-cyano-1,3-butadienyl]-2,2-dimethylcyclopropanecarboxylic acid chloride represented by the following formula:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC.[Cl-].[Li+]>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH:9]([C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)=[CH2:10]
Reactant: Nc1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N)nc1
Yield: 57.4 %

Procedure:
5-Bromopyridine-2-amine (2.51 g) was dissolved in toluene (150 mL), tributylvinyl tin (10.0 g), lithium chloride (1.23 g) and 2,6-di-tert-butyl-4-methylphenol (160 mg) were added and the mixture was heated under reflux for 2 hr 30 min. The resulting solid was removed by filtration, and the solvent was evaporated. The residue was dissolved in ethyl acetate and the insoluble material was removed again by filtration. The filtrate was extracted with 0.2 mol/L hydrochloric acid (100 mL, 50 mL), and the obtained hydrochloric acid solution was basified (pH 12) with 1 mol/L sodium hydroxide, extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 5-vinylpyridine-2-amine (1.00 g). This was dissolved in ethyl acetate (80 mL). Under a nitrogen atmosphere, 10% palladium-carbon (330 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 8 hr. The reaction container was substituted with nitrogen (gas) and 10%-palladium carbon (300 mg) was added. The mixture was stirred under a hydrogen atmosphere for 4 hr. The reaction container was substituted with nitrogen (gas) and the catalyst was filtered off. The solvent was evaporated and the residue was dissolved in 0.4 mol/L hydrochloric acid (20 mL). The obtained hydrochloric acid solution was washed with ethyl acetate, basified (pH 12) with 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (773 mg).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[CH3:25][C:26]([CH3:29])([O-])[CH3:27].[K+].BrCC(C)C>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:25][CH:26]([CH3:29])[CH3:27])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[O-]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [K+]
Solvent: CC(C)CBr
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) (78 mg, 0.22 mmol) in 480 μL of DMF was added potassium tert-butoxide (40 mg, 0.54 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then treated with 1-bromo-2-methylpropane (82 μL, 0.76 mmol). After being stirred at 25° C. for 4 h, the reaction was quenched with sat. aqueous NaHCO3 and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel prep plate (25% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)=O.[SH2]=N.[C:13]1([NH:19][C:20](C2C=CC=CC=2C(O)=O)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([NH:19][C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: C1COCCN1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)N1CCOCC1
Yield: 32.8 %

Procedure:
A solution of 0.9 g morpholine with 5 ml aceton was added dropwise during 5 minutes to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml acetone, under stirring. The reaction mixture was stirred for a further 30 minutes at ambient temperature, then diluted with 150 ml water. Acetone was distilled off, the mixture was cooled, and 0.35 g phenylcarbamoyl-morpholine was isolated by filtration. The white crystalline material melted at 160°-162° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[F:17].[NH3:18].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:18])=[C:4]([F:17])[C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 1-(bromomethyl)-4-chloro-2-fluoro-3-(phenyloxy)benzene (0.058 g, 0.184 mmol) and 7M ammonia in methanol (3 mL, 21.00 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.023 g, 47% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 7.93 (br. s., 2H), 7.52-7.60 (m, 1H), 7.46 (t, 1H), 7.26-7.38 (m, 2H), 7.01-7.12 (m, 1H), 6.86 (d, 2H), 4.07 (s, 2 H). ES MS: m/z 252 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.C[Mg]Br.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[C:7]2[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:16]=1[Cl:15])=[O:19]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cc2cccc(Br)c2[nH]1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1[nH]c2c(Br)cccc2c1C(=O)c1cccc(Cl)c1Cl
Temperature: -10 °C

Procedure:
10.7 g of 7-bromo-2-methyl-1H-indole are placed in 100 ml of THF and the mixture is cooled to −10° C. 22 ml of 3M methylmagnesium bromide in ether are added at this temperature. The mixture is allowed to return to AT and is then cooled to −5° C. and 13.5 g of 2,3-dichlorobenzoyl chloride, dissolved in 80 ml of THF, are added dropwise. The medium is allowed to return to AT and is then poured onto a saturated NH4Cl solution. Extraction is carried out with ether and then the organic phase is washed with a 10% NaOH solution, water and a saturated NaCl solution. It is dried and evaporated and the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (10/90, v/v) mixture. The product obtained crystallizes from ether and 5 g of the expected compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCOCC>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][OH:9]
Reactant: OCCC1CCCCN1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: CCOCC
Product: OCC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 6.2 %

Procedure:
Piperidine-2-ethanol (127 g, 980 mmol) in 95% EtOH (260 mL) was added to (S)-(+)-camphorsulfonic acid (228.7 g, 1.0 eq.) in 95% EtOH (150 mL) and the resulting solution was warmed to reflux. To the warm solution was added Et2O (600 mL) and the solution cooled to room temperature and let stand 3 days. The resulting crystals were filtered and dried in vacuo (25 g): mp 173–173° C. (lit. 168° C.). The salt was then dissolved in NaOH (3M, 100 mL) and stirred 2 hours and the resulting solution was extracted with CH2Cl2 (5×100 mL). The combined organics were dried over Na2SO4, filtered, filtered and concentrated under reduced pressure to give (S)-piperidine-2-ethanol (7.8 g) a portion of which was recrystallized from Et2O: mp=69–70° C. (lit. 68–69° C.); [α]D=14.090 (CHCl3 c=0.2).
Reaction SMILES: [CH3:1][C@@:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@@:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][NH:3]1
Reactant: COC(=O)[C@]1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]1(C)CC(C)(C)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate 106D in CH2Cl2 (60 ml) was added TFA (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was used for the next step without purification.