Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Reactant: CN1CCNCC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCN3CCN(C)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and 1-methyl-piperazine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C26H39N7O4SF [(M+H)+]564.2767, observed 564.2763.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[NH2:13][C:14]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:15]([NH2:17])=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:15]([C:14]([N:13]=[CH:1][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([CH3:21])[CH:18]([CH3:20])[CH3:19])(=[O:16])[NH2:17]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: COC(=O)c1ccccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1C=NC(C)(C(N)=O)C(C)C
Reaction time: 3 h

Procedure:
A mixture containing 5.0 g methyl 2-formylbenzoate [C. Brown and M. V. Sargent, J. Chem. Soc. (C), 1818 (1969)] and 4.0 g 2-amino-2,3-dimethylbutyramide and 50 mg p-toluenesulfonic acid in 100 mL toluene is heated under reflux under a Dean-Stark water separator for three hours. The mixture is filtered and concentrated in vacuo. The residue crystallizes on standing and is recrystallized from etherhexane to give analytically pure methyl o-[N-(1-carbamoyl-1,2-dimethylpropyl)formimidoyl]benzoate, mp 79°-80.5° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:23][CH3:24])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]([CH3:20])=[C:15]([CH3:21])[C:14]=2[CH:22]=1)(=O)=O.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>CO.C(O)C>[CH3:24][O:23][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:14]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CO
Product: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 64 %

Procedure:
Method A (45 h at 50° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (example 75) and 1-phenylpiperazine; yield 64%; fusion point 151°-152° C. (from ethanol and methanol). Fumarate (×0.5 C4H4O4): method E; yield 92%; fusion point 207°-209° C. (from ethanol and methanol).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11]C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[CH:10]=[O:11]
Reactant: COc1ccc(I)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(I)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.04 grams (8.72 mmol) of 4-iodoanisole in 36 mL of CH2Cl2, cooled to 0° C., was added dropwise 2.0 mL (18.7 mmol) of titanium tetrachloride. After stirring for 30 min., 0.93 mL (10.3 mmol) of α, α-dichloromethyl methyl ether was added and the reaction maintained at 0° C. for another 2 hours. The reaction mixture was then poured with stirring into a mixture of 50 mL of CH2Cl2 and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3). After 30 min., this was filtered through diatomaceous earth, the organic layer was separated, the aqueous layer was twice extracted with CH2Cl2, and all of the organic layers were combined, dried with MgSO4 and concentrated in vacuo. The crude residue was recrystallized from ethanol (EtOH) to give 5-iodo-2-methoxybenzaldehyde as pale yellow needles, 1.37 grams (60%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([C:15]([N:17]([CH3:24])[CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:16])[CH:14]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[N:31]#[C:32]Br>CN(C=O)C>[C:32]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]([CH3:24])[C:15]([N:13]2[CH:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:12]2)=[O:16])[CH2:19][CH2:20]1)#[N:31]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCNCC3)cn2)cc1
Reactant: N#CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCN(C#N)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-methoxyphenyl)-N-methyl-N-(piperidin-4-yl)-1H-imidazole-1-carboxamide hydrochloride (287 mg, 0.818 mmol) in DMF (5 mL) was added potassium tert-butoxide (184 mg, 1.636 mmol) and the mixture was allowed to stir at room temperature for 30 minutes, whereupon it was cooled in an ice/water bath and cyanogen bromide (0.818 mL, 2.454 mmol, 3 N dichloromethane solution) was added dropwise over 10-15 minutes. The reaction mixture was allowed to slowly warm up to room temperature over 1 h, and was then partitioned between water and dichloromethane/isopropanol (7:3). The layers were separated and the organic phase was further washed with water and brine, then dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was dissolved in the minimum volume of chloroform and insoluble material was removed by filtration. The filtrate was concentrated to give an off-white solid, (345 mg, 67%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7](OCC)=[O:8])(=[O:4])=[O:3].[CH:24]1([C:27]2[C:28]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:37]3[CH2:42][CH2:41][N:40]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:22])=[O:23])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:8])[CH2:39][CH2:38]3)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 58.5 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (181 mg) described in Preparation Example 28 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (136 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 109, the title compound (172 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:37]=[CH:36][CH:35]=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)c1cccc(CSc2c(Cl)ccc3c2CCNCC3)c1
Product: Cl

Procedure:
Use a method similar to the Example 347 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with methyl 3-(bromomethyl)benzoate. Use a method similar to the General Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give the title compound. MS (APCI+) m/z: 362 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](C=O)[C:5]=2[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2.[Br:17]C1C=CC=C2C=1CCC(=O)C2.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[Br:17][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:1]2
Reactant: O=Cc1cccc2c1CCC1(C2)OCCO1
Reactant: O=C1CCc2c(Br)cccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: OCCO
Product: Brc1cccc2c1CCC1(C2)OCCO1
Yield: 98 %

Procedure:
3′,4′-Dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-5′-carbaldehyde, designated as 37 in FIG. 15, was prepared as follows: A solution of 5-bromo-3,4-dihydronaphthalen-2(1H)-one (625 mg, 2.78 mmol), ethylene glycol (0.23 mL, 4.17 mmol), and p-toluenesulfonic acid (5.70 mg, 0.03 mol) in benzene (46 mL) was stirred and heated to reflux for 10 h. The solution was cooled, diluted with ether, and sequentially washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography, using a 2:1 mixture of hexanes and AcOEt as eluant, furnished 5′-bromo-3′,4′-dihydro-1′H-spiro[[1,3]-dioxolane-2,2′-naphthalene](730.4 mg, 98% yield) as a yellow oil. Yield: 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([N:25]([CH3:27])[CH3:26])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[OH:24].CC([O-])(C)C.[K+].O>CS(C)=O>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH:17]([N:25]([CH3:27])[CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10]
Reactant: CN(C)C(c1ccccc1Cl)C1CCCCC1O
Reactant: ClCc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(c1ccccc1Cl)C1CCCCC1OCc1ccccc1Cl
Product: Cl
Temperature: 100 °C
Yield: 12.6 %

Procedure:
902 mg (5.60 mmole) of 2-chlorobenzyl chloride and 1.0 g (3.73 mmole) 2-[(2-chlorophenyl)dimethylaminomethyl]-cyclohexanol were dissolved in 6.0 ml dimethylsulfoxide, analytical grade, 503 mg (4.48 mmole) solid potassium tert-butylate were added, under nitrogen, and the mixture was heated at 100° C. for 15 hours. For working up, 10 ml water were added, and the mixture was extracted three times with 15 ml ether each time. The combined extracts were washed with 10 ml each of potassium hydroxide solution (2 M) and water and extracted three times with 25 ml hydrochloric acid (5 wt. %) each time. The combined acid extracts were rendered alkaline (pH≧11) with sodium hydroxide solution (32 wt. %) and extracted three times with 25 ml methylene chloride each time. The combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 277 mg crude base were obtained. 151 mg {[2-(2-chlorobenzyloxy)cyclohexyl]-(2-chlorophenyl)methyl}-dimethylamine hydrochloride (9.4% of theoretical) with a melting range of 108-100° C. were obtained from this crude base in accordance with Example 1 (4th stage) using chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[CH3:10][CH:11]([S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12].[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]([CH:17]2[CH2:19][CH2:18]2)[NH:16][S:13]([CH:11]([CH3:12])[CH3:10])(=[O:15])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cncc(Br)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Temperature: -40 °C
Yield: 66 %

Procedure:
A mixture of 5-bromonicotinaldehyde (0.930 g, 5 mmol), propane-2-sulfonamide (0.616 g, 5.00 mmol) and titanium(IV) isopropoxide (2.93 mL, 10.00 mmol) in toluene (20 mL) was heated to reflux for 4 h. After concentration, the residue was dissolved in THF (25 mL) and cooled to −40° C. A solution of cyclopropylmagnesium bromide (25 mL, 12.50 mmol) was added dropwise and the resulting mixture was slowly warmed up to 0° C. over 4 h. After quenching with a NH4Cl solution, filtration and extraction with CH2Cl2, the organic phase was dried over Na2SO4, filtered and concentrated, to give a residue which was purified by flash column (ethyl acetate/heptane, v/v, 10%-35%) and to give a yellow solid (1.1 g). ESI-MS m/z: 335.0 [M+1]+.
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33]C)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:35]([O:37]C)=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O.CO.O1CCCC1>[C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH2:33])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:11]([C:35]([OH:37])=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Yield: 98.9 %

Procedure:
The procedure of Example 42 was followed using the product from Example 40 (270 mg, 0.521 mmol), lithium hydroxide (55 mg, 1.3 mmol) in water (0.4 ml), methanol (1 ml) and tetrahydrofuran (1 ml) to give 260 mg (99%) of the product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:23]3[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]3)=[O:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@H]1CNCCN1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Product: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)CCN1

Procedure:
The title compound (D16) was prepared from 1-(4-cyanophenyl)-piperidine4-carboxylic acid (D3) and (R)-2-methylpiperazine using the procedure of Description D15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=C)=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O.C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=[O:27])=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:24][CH:25]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)cnc32)cc1
Reaction time: 4 h
Yield: 103.5 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylpyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 30, 3.96 g, 11.9 mmol) was suspended in THF (80 mL) and heated with a heat gun to effect dissolution. Similarly, sodium periodate (5.84 g, 27.3 mmol) was heated in water (40 mL) to effect dissolution. The above solutions were combined with vigorous stirring. While the stirred mixture was still at 40° C., osmium(VIII) oxide in ten-butanol (2.90 mL, 2.5%, 0.30 mmol) was added and the mixture was stirred vigorously for 4 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3×150 mL) and DCM (3×150 mL). The combined organic layers were dried (MgSO4) and concentrated to afford the title compound (4.13 g, 99%) as a black solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 5.80 (s, 2H), 6.83 (d, J=8.66 Hz, 2H), 7.61 (d, J=8.66 Hz, 2H), 8.41 (s, 1H), 9.10 (d, J=2.13 Hz, 1H), 9.26 (d, J=2.13 Hz, 1H), 10.21 (s, 1H). [M+H]=336.2.
Reaction SMILES: Br[C@@H:2]1[C@@H:8]([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1.CO>[OH:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)[C@H]1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)C1
Yield: 80.8 %

Procedure:
To a solution of 2-((1R,2S,3S)-2-bromo-3-hydroxycycloheptyl)isoindoline-1,3-dione (4.2 g, 12.42 mmol) in toluene (69 mL) and methanol (6.9 mL) was added tributyltin hydride (4.34 mL, 16.14 mmol) via syringe over 10 minutes under nitrogen followed by 2,2′-azobis(2-methylpropanenitrile) (0.204 g, 1.242 mmol) in one portion. The reaction was then heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was concentrated to dryness under reduced pressure to afford a residue that was purified by silica gel chromatography (0-50% ethyl acetate in hexanes). Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (2.6 g, 10.03 mmol, 81% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72-7.98 (m, 4H), 4.58 (d, J=4.29 Hz, 1H), 4.14 (br. s., 1H), 3.67 (dt, J=6.25, 3.90 Hz, 1H), 2.24-2.40 (m, 1H), 2.04-2.19 (m, 1H), 1.81-1.95 (m, 2H), 1.39-1.80 (m, 6H). MS (ESI) m/z 259.9 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](C(C)=O)[CH3:8].C(I)C.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>O>[CH2:7]([O:23][C:19]1[CH:18]=[C:17]([C:16]([F:24])([F:25])[F:15])[CH:22]=[CH:21][CH:20]=1)[CH3:8]
Reactant: CCC(C)=O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCOc1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Potassium carbonate (22.6 g) and then a mixture of methyl ethyl ketone (MEK) (150 mL) and ethyl iodide (47.8 g) were added to a mixture of MEK (310 mL) and 3-trifluoromethylphenol (a) (25.0 g) at room temperature, and the reaction mixture was heated and stirred for 2 hours. After returning the mixture to room temperature, water was added for liquid separation and the aqueous layer was extracted three times with diethyl ether. The organic layers were combined, washed with an 1 M aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.3 g of Compound (b).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39]OS1(=O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:39][CH2:40][NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1CCNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
The solution of 7.0 g (21.9 mmol) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole-2-carboxylic acid ethyl ester in 60 mL N,N-dimethylformamide was cooled down to 0° C. and 2.7 g (24.1 mmol) potassium tert-butoxide was added. After 30 min., 5.4 g (24.2 mmol) 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO 02/072584) was added and the cooling bath was removed. After 1.5 hours, 10% aqueous ammonium chloride solution was added and the two-phase mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The thus obtained crude product (brown oil; 12.0 g, 100%) was used without further purification for the next step.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH3:57][O:58][C:59]1[N:64]=[C:63]([CH:65]=O)[CH:62]=[CH:61][CH:60]=1>>[Cl:55][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=1[Cl:54])[CH2:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([C@H:38]2[CH2:37][O:36][C:32]3=[CH:33][C:34]4[CH2:35][C@@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([O:14][C:15]6[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=6[CH3:22])=[CH:12][CH:13]=5)[C:5]([OH:4])=[O:56])=[O:25])[N:27]([CH2:65][C:63]5[CH:62]=[CH:61][CH:60]=[C:59]([O:58][CH3:57])[N:64]=5)[CH2:28][C:29]=4[CH:30]=[C:31]3[O:39]2)=[CH:45][CH:44]=1
Reactant: COc1cccc(C=O)n1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COc1cccc(CN2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)n1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride (30 mg) was reductively aminated with 6-methoxy-pyridine-2-carbaldehyde according to General Procedure D (with excess of aldehyde). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 876.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[C:27]([O:34][CH3:35])(=[O:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH:22]=[C:28]([C:27]([O:34][CH3:35])=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(OCCOc3ccc(C=O)cc3)ccc21
Reactant: COC(=O)CC(=O)OC
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a solution of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzaldehyde (1.50 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution is concentrated under a vacuum to give title compound (1.95 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:27]([C:26]2[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=[CH:24][C:25]=2[C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: Fc1cc(C(F)(F)F)ccc1N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine (Example F) and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 514.3 MH+.