Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23]Br)[CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:5])[CH3:2].[O-]CC.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:23][CH2:22][N:9]([CH2:10][CH2:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCN(CCBr)CCC1COc2ccccc2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3C2)CC1
Temperature: 25 °C

Procedure:
At room temperature and while stirring, a solution of 11.94 g (30 mmol) of N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]amine in 40 ml of absolute dimethylformamide is added dropwise within a period of 20 minutes to a suspension of 2.72 g (40 mmol) of sodium ethoxide in 30 ml of dimethylformamide. The reaction mixture is stirred for 16 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl ether is added to the residue and extraction is carried out with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The crude product is obtained as the residue and is chromatographed on 500 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. The eluate is concentrated by evaporation to yield 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester in the form of a colourless oil. The 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182°-186°.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][N:8]1[C:7]2[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=[CH:5][C:6]=2[S:10][C:9]1=[O:11]
Reactant: COC(=O)c1ccc2sc(=O)[nH]c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc2sc(=O)n(C)c2c1C
Yield: 84.3 %

Procedure:
A solution of 11.38 g (51 mmol) of methyl 4-methylbenzo-thiazol-2-one-5-carboxylate in 400 ml of acetone was admixed with 14.18 g of potassium carbonate. 5.1 ml (54 mmol) of dimethyl sulfate were then added dropwise with stirring, and the mixture was stirred at 23° C. for 78 hours. The precipitated solid was filtered off and the solvent was removed under reduced pressure. Recrystallization from ether gave, in a yield of 84%, 10.15 g (43 mmol) of methyl 3,4-dimethylbenzothiazol-2-one-5-carboxylate of m.p. 97° C.-100° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>N12CCCN=C1CCCCC2.C(O)(=O)C>[CH2:8]([O:7][C:5](=[O:6])[C:4]([C:10](=[O:12])[CH3:11])([C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CCOC(=O)CCC(C(C)=O)(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
2.0 g of ethyl 2-acetyl-3-oxo-butyrate was mixed with 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene. Over 10 minutes, 2.7 g of ethyl acrylate was added dropwise. The mixture was stirred for 30 hours at room temperature, 2 ml of acetic acid was added to neutralize the base, and the mixture was extracted with an aqueous sodium carbonate solution and water. Fractional distillation yields 1.5 g of 2,2-diacetyl-1,5-pentanedioic acid diethyl ester (purity: 70%; colorless).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=[C:14]3[NH:24][CH:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)[C:13]=23)[CH2:8][CH2:7]1)=[O:5].[CH3:36][C:37]([CH3:39])=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)Cl.CCOCC.CO.CN(C=O)C.ClCCCl>[CH:37]([NH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][N:15]=[C:14]3[NH:24][CH:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)[C:13]=23)[CH2:8][CH2:7]1)=[O:5])([CH3:39])[CH3:36]
Reactant: NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 0.5 h
Yield: 7.5 %

Procedure:
N-(4-(4-(3-Aminopropanoyl)piperazin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.015 g, 0.026 mmol, see Example 65) and acetone (0.0150 g, 0.259 mmol) were placed in 1:1 DCE:DMF (2 mL). DIEA (d 0.742; 0.0226 mL, 0.130 mmol) was then added, followed by the addition of NaBH(OAc)3 (0.0110 g, 0.0518 mmol). The reaction was then stirred for 30 minutes, and poured into Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated. The residue was purified by reverse phase HPLC to give the product. The product was then dissolved in minimal DCM and MeOH and added to a stirring solution of 1M HCl in ether. The resulting solid was collected to give N-(4-(4-(3-(isopropylamino)propanoyl)piperazin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.001 g, 6.2% yield) as the trihydrochloride salt. MS APCI (+) m/z 512 detected.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.O.C(N(CC)CC)C.CO>[C:13]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To the solution of D-Serine (100 g; 0.95 moles) in dichloromethane (1.0 L), trimethylsilyl chloride (361.79 g) was added in 15 minutes to 30 minutes. It was refluxed at 40° C. for 20 minutes and then cooled to ambient temperature. To the resultant solution, triethyl amine (433.27 g) dissolved in dichloromethane (200 ml) was added in 60 minutes to 90 minutes. It was refluxed at 40° C. to 45° C. for 2 hours and then cooled to 0° C. to −2° C. To the cooled solution, methanol (45.72 g) diluted with dichloromethane (200 ml) was added in 60 minutes to 75 minutes (exothermic reaction was observed). It was stirred for 15 minutes at 0° C. to 5° C. and then further raised to ambient temperature. At this temperature, triethyl amine (96.28 g) was added in 15 minutes to 20 minutes and stirred for 10 minutes. To the resultant reaction mixture, trityl chloride (238.78 g; 0.85 moles) was added in 6 lots at an interval of 10 minutes at ambient temperature and stirred for 3 hours. The reaction mixture was cooled to 5° C. and de-ionized water (500 ml) was added to it at 5° C. to 10° C. The reaction mixture was stirred for 15 minutes at the same temperature and allowed to settle for 15 minutes. The organic layer (dichloromethane layer) was separated and 5% citric acid monohydrate solution (500 ml) was added for 5 minutes to 10 minutes, stirred for 15 minutes at 5° C. to 10° C. and allowed to settle for 15 minutes. The organic layer (dichloromethane layer) was separated and de-ionized water (500 ml) was added at 5° C. to 10° C. for 10 minutes to 15 minutes, stirred for 15 minutes and allowed to settle. The organic layer obtained was separated and solvent was recovered at atmospheric pressure up to 45° C. Traces of solvent (if any) were recovered under vacuum at 35° C. to 40° C. To the remaining residue, toluene (100 ml) was added and heated to 50° C. under stirring for 15 minutes. The solvent was recovered under vacuum at 45° C. to 50° C. Toluene (250 ml) was again added to the residue at 50° C. and it was stirred for 15 minutes. This was cooled to ambient temperature and then hexanes (500 ml) were added. The mixture was stirred for 30 minutes and cooled further to 0° C. to 5° C. It was stirred at this temperature for 30 minutes. The solid obtained was filtered, washed with hexanes (200 ml) and suck dried. It was further dried in a vacuum tray dryer at 50° C. to 55° C. until moisture content was NMT 0.5%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].Cl.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)#[N:11]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]([C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCNCCC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CCC(=O)O)C(=O)c1ccc(C#N)cc1
Yield: 56 %

Procedure:
A suspension of ethyl β-alanine.HCl (2.81 g, 18.3 mmol) and 4-cyano-benzoyl chloride (3.03 g, 18.0 mmol) in DCM (30 mL) was stirred overnight at RT. The mixture was diluted with EtOAc, washed with aq. citric acid (3%), sat. aq. NaHCO3 and H2O. Drying (MgSO4) and evaporation of the solvent gave compound 2 (2.52 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([Cl:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([Cl:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Fc1ccc(CNc2nc(-c3ccno3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7]([CH3:9])=[CH:6]O[CH:4]1OC)[CH3:2].[N+:12]([O-])([O-])=O.[NH4+]>O.C(O)(=O)C.[N+]([O-])(O)=O>[CH2:1]([C:3]1[CH:4]=[N:12][CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2]
Reactant: CCC1CC(C)=COC1OC
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CCc1cncc(C)c1
Reaction time: 0.25 h
Yield: 66 %

Procedure:
156 parts of 3-ethyl-2,3-dihydro-2-methoxy-5-methyl-4H-pyran are dissolved in 25 parts of water, 300 parts of acetic acid and 2 parts of 60 percent strength nitric acid at 22° C. After 15 minutes, a solution of 80 parts of ammonium nitrate in 80 parts of water is added. The resulting solution is added to 800 parts of acetic acid at 110° C. in the course of 20 minutes, whilst stirring. The reaction mixture is left to cool, the acetic acid, water and methanol are distilled off, 200 parts of water are added to the residue and the solution is rendered alkaline with 25 percent strength ammonia solution. The 3-ethyl-5-methyl-pyridine is extracted with ether. Distillation gives 80 parts (66% of theory) of 3-ethyl-5-methyl-pyridine of boiling point 83° C./15 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3F)CC2)c(C)c1
Yield: 74.4 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (317 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Temperature: 70 °C
Yield: 97 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (260 mg, 0.60 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (6 mL of 1 M in THF solution, 6.00 mmol) and molecular sieves. The solution was heated under reflux (70° C.) for 4 hours without stirring. The solution was cooled to ambient temperature and acidified to pH=5 by adding dropwise a dilute solution of acetic acid in MeOH. The solution was filtered and the filtrate was concentrated via rotary evaporation. The material was extracted into EtOAc and washed 3×H2O. The organic layer was dried over Na2SO4 and concentrated down to afford 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine as an orange solid (177 mg, 97% yield). MS: m/z 303.9, 305.9 [M+H+]. The material was used directly in step 2 without further purification.
Reaction SMILES: [CH:1]1[C:6](S([O-])(=O)=O)=[CH:5][C:4]2[C:11](/[C:13](/[NH:28][C:3]=2[CH:2]=1)=[C:14]1/[C:15]([C:17]2[CH:18]=[C:19](S([O-])(=O)=O)[CH:20]=[CH:21][C:22]=2[NH:23]/1)=[O:16])=[O:12].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH:6]1[CH:5]=[C:4]2[C:11]([OH:12])=[C:13]([C:14]3[NH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:15]=3[OH:16])[NH:28][C:3]2=[CH:2][CH:1]=1
Reactant: O=C1/C(=C2\Nc3ccc(S(=O)(=O)[O-])cc3C2=O)Nc2ccc(S(=O)(=O)[O-])cc21
Agent: *CC*
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: Oc1c(-c2[nH]c3ccccc3c2O)[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution prepared by dissolving 0.2 grams of indigo carmine (a sulfonated indigo, C.I. 1180) and one gram of sodium carbonate in 500 grams of water was titrated with sodium hydrosulfite (Na2S2O4) to the disappearance of the blue color. Portions of this solution of 150 grams each were placed in matched 250 ml glass beakers. On one portion was floated 5 grams of polyethylene beads. On another portion was floated 5 grams of activated carbon wetproofed with 2% of PTFE. On a third portion was floated 5 grams of activated carbon wetproofed with 10% of PTFE. After a few minutes, the solution under the carbon wetproofed with 2PTFE showed streamers of blue color from the top extending nearly to the bottom of the beaker, while at the same time the solution under the carbon wetproofed with 10% PTFE showed fewer streamers of blue color from the top, not reaching to the bottom, and the solution under the polyethylene beads showed only a thin blue film at the interface. After about 30 minutes, both of the solutions under floating carbon were deep blue, while the solution under the polyethylene beads was not significantly bluer than earlier.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:47]=1)[O:27][CH2:28][C:29]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:47]=1)[O:27][CH2:28][C:29]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CC1(C)OB(/C=C2\c3ccc(F)cc3COc3cc(F)ccc32)OC1(C)C
Reactant: C[C@H](CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CN1CCOCC1)Nc1ccc(/C=C2\c3ccc(F)cc3COc3cc(F)ccc32)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 48.5 %

Procedure:
Degas three times a mixture of (R)-(4-bromo-2-nitro-phenyl)-(1-methyl-2-morpholin-4-yl-ethyl)-amine (0.037 mol, 12.8 g), (E)-3,8-difluoro-11-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-ylmethylene)-6,11-dihydro-dibenzo[b,e]oxepine (0.037 mol, 13.7 g), triphenylphosphine (0.007 mol, 2.02 g) and potassium acetate (0.074 mol, 7.29 g) in dioxane/water (3:1) (450 mL) with nitrogen. Add palladium (II) acetate (0.001 mol) to the reaction mixture and degas again three times with nitrogen. Heat the resulting reaction mixture at 85° C. for 16 h. Cool the reaction mixture to room temperature, dilute with water, extract with ethyl acetate, combine organic layer, wash with water and brine. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 7% ethyl acetate in hexanes as eluent to obtain the title compound (9.1 g, 48%) as an orange solid. 1H NMR (400 MHz, CDCl3), δ 1.26 (d, 3H), 2.44-2.57 (m, 6H), 3.66-3.68 (m, 4H), 3.71-3.78 (m, 1H), 4.89 (br s, 1H), 5.63 (br s, 1H), 6.52 (dd, 1H), 6.61 (d, 1H), 6.67 (dt, 1H), 6.76 (s, 1H), 6.89 (d, 1H), 6.95 (dt, 1H), 7.06-7.10 (m, 1H), 7.19 (dd, 1H), 7.29-7.41 (m, 1H), 7.95 (d, 1H), 8.35 (d, 1H, —NH).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[CH3:18].Br>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH3:18]
Reactant: COc1ccc(C2(C)Cc3cc(OCC(=O)O)c(Cl)c(Cl)c3C2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC1(c2ccc(O)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
A stirred mixture of [1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid (1.80 g., 0.0046 mole), Example 8, Step E, 48% hydrobromic acid (50 ml.) and acetic acid (50 ml.) is heated at reflux for one hour, then poured into crushed ice-water (800 ml.) to precipitate 900 mg. of [1-oxo-2-(4-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid which melts at 220°-222° C. after crystallization from acetic acid: water, 1:1, and nitromethane.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 99° C. and MS: m/e=369 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C([NH:5][C:6](=[O:19])[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:8]=1[F:18])(C)(C)C>C(O)(C(F)(F)F)=O>[C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([C:6]([NH2:5])=[O:19])=[C:8]([F:18])[CH:9]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cc(C(C)(C)C)cc(F)c1C(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)(C)C)cc(F)c1C(N)=O
Yield: 81 %

Procedure:
A solution of N,4-di-tert-butyl-2-fluoro-6-methylbenzamide (4.01 g, 15.1 mmol, Eq: 1.00) in TFA (48 ml) (4×12 mL, microwave vials) was stirred at 100° C. for 3 h under microwave assisted conditions. The contents of the four microwave vials were combined, evaporated under vacuum and residue was poured (carefully) into an aqueous saturated solution of NaHCO3 (100 mL) and the product was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated under vacuum. The crude material was purified by chromatography (SiO2, CH2Cl2 100% to 30% AcOEt, in 30 min) to afford the desired product (2.55 g, 81% yield as a white solid. LC/MS, m/z 210[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9 H) 2.49 (t, J=0.63 Hz, 3 H) 5.86 (br. s., 2 H) 6.94-7.00 (m, 1 H) 7.05 (dd, J=1.26, 0.51 Hz, 1 H).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:8][C:7]1=[O:23])(=O)[CH2:2][CH2:3][CH3:4].[CH2:24]([O:27][NH2:28])[CH:25]=[CH2:26]>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:8][C:7]1=[O:23])[CH2:2][CH2:3][CH3:4])[CH:25]=[CH2:26]
Reactant: CCCC(=O)C1C(=O)CC(CCS(C)(=O)=O)C(C(=O)OC)C1=O
Reactant: C=CCON
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCS(C)(=O)=O)C(C(=O)OC)C1=O

Procedure:
3.5 g of 2-butyryl-5-(2-methylsulfonylethyl)-4-methoxycarbonyl-cyclohexane-1,3-dione was allowed to react with 0.9 g of allyloxyamine at room temperature for 5 hours in 20 ml of ethanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain 3.1 g of white crystal of the desired compound. m.p. 96.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH:26]([CH3:37])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH:26]([CH3:37])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Solvent: C1COCCO1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)NC1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
The more nonpolar diastereoisomer of N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (109 mg, 0.5 mmole) was added to a solution of [2-(1H-indol-3-yl)-1-methyl-ethyl]-carbamic acid phenyl ester (147 mg, 0.5 mmole) in dioxane (10 ml). The batch was then refluxed for 6 h. Working up was performed by removing dioxane by distillation and diluting the batch with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(1H-indol-3-yl)-1-methylethyl]urea was obtained after chromatography on silica gel with methanol as a colorless oil in a yield of 125 mg (60%).