Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[O:7][C@H:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])[O:9][C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.C(N(CC)CC)C>CCO.[Pd]>[ClH:2].[C:11]1([C@H:10]2[C:5]3[CH:4]=[CH:3][CH:27]=[CH:26][C:6]=3[O:7][C@H:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])[O:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCCNC(=O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2)O1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)CCCNC(=O)[C@H]1Oc2ccccc2[C@H](c2ccccc2)O1

Procedure:
trans-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)1,3-benzodioxan-2-carboxamide hydrochloride (1.0 g., 2.43 mmole) was mixed with triethylamine (0.526 g., 5.2 mmole) and 30% Pd on Celite catalyst (0.3 g.,) in 200 ml of absolute EtOH and hydrogenated in a Parr apparatus for 30 mins. at an initial H2 pressure of 48 psi. The uptake was 13 lbs. of H2 and after catalyst removal, the filtrate was stripped of solvent under reduced pressure. The residue was partitioned between CH2Cl2 and 2% Na2CO3 solution. After extraction of the aqueous with a second portion of CH2Cl2, the organics were combined, washed with H2O, dried (MgSO4) and stripped to a syrup under reduced pressure. The .HCL salt was formed in CH2Cl2 in the usual manner, and after solvent removal, crystallization was effected by trituration in hot EtOAc, followed by cooling (0.66 g., 72%). Recrystallization from EtOAc-abs EtOH gave analytical material (mp 165°-170° d).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:21][O:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC1(c2ccccc2)CCNCC1
Reaction time: 1 h
Yield: 108.8 %

Procedure:
4-Methoxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (0.35 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 3 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound as a white solid (0.25 g). LCMS m/z 192.2[M+H]+. R.T.=1.96 min (Analytical Method 4).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[CH:17]=[C:16]([C:29]([O:31]CC)=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:7]=1)[CH3:2].C1COCC1.[Li+].[OH-]>CO>[CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:39]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCC[C@@H]2O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@@H]2CCCC[C@@H]2O)cn1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(cis-2-hydroxycyclohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 253, 0.240 g, 0.38 mmol) was suspended in MeOH (6 mL) in a microwave vessel (CEM). THF (3.00 mL) was added. A 2.0 M aq solution of LiOH (0.381 mL, 0.76 mmol) was added. The microwave vessel was heated in the microwave at 100° C. for 15 min After cooling to room temperature, the solvent was removed in vacuo to give a residue which was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(cis-2-hydroxycyclohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.113 g, 49%).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.COCCOC.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: On1nnc2ccccc21
Solvent: COCCOC
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)On1nnc2ccccc21
Temperature: 21 °C

Procedure:
To a mixture of 1-hydroxybenzotriazole (30.6 g), 1,2-dimethoxyethane (150 ml), and pyridine (16 g), there was added, while stirring at 21° C., pivaloyl chloride (24.1 g) during 0.75 hr. During the addition, the temperature of the reaction mixture was raised to 34° C. by the heat evolved. The reaction was then heated externally at 88° C. for an additional 0.5 hr. period then cooled, washed with water, and extracted with 1,1,2-trichlorotrifluoroethane. The extract was dried and stripped of solvent and the residue was column chromatographed on neutral alumina in benzene solvent. The product, 1-benzotriazolyl pivalate, was obtained as a brown oil after removal of the benzene solvent. The elemental analysis was as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=2)=[N:9][N:8]=1.C(N(CC)CC)C.[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:37](=[O:38])[CH2:36][CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:13]=2)=[N:9][N:8]=1
Reactant: Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.6 %

Procedure:
To a solution of 4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (360 mg, 1.19 mmol) and triethylamine (290 mg, 2.86 mmol) in tetrahydrofuran (30 mL) was added 3-phenylpropionyl chloride (482 mg, 2.86 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (205 mg, yield 40%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=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.CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1c(F)cccc1Br
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: CO
Solvent: Cc1ccccc1
Product: N#Cc1c(F)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound, 2-Bromo-6-fluorobenzonitrile, the procedure for the preparation of which may be found in Hynes, John B. et. al., J. Hetercycl. Chem. 1988, 25, 1173-7, (2.0 g, 10.0 mmol) and phenylboronic acid (3.66 g, 30 mmol) were added to a mixture of toluene (80 mL), methanol (20 mL), and 2 M aqueous sodium carbonate (20 mL). This mixture was refluxed while stirring under argon for 15 min. The resulting mixture was cooled to room temperature and tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1 mmol) was added. The resulting mixture was then refluxed for 12 hours while stirring under argon. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (2×), brine (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0-10% methylene chloride in hexane. Recrystallization from methylene chloride hexane gave the title product as a white crystalline solid. mp 78-79° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][C:16]=1[O:24][CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:17][C:16]=1[O:24][CH3:25]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
A mixture of 2.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid, 1.7 g of 2-(4-hydroxy-3-methoxyphenyl)-ethylamine, 4.6 g of (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 4.5 ml of N,N-diisopropylethylamine is stirred in 40 ml of N,N-dimethylformamide at room temperature for 2 hours. The reaction mixture is introduced into 500 ml of water and extracted twice with 400 ml of ethyl acetate each time. The organic phases are washed once with 300 ml of water and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. (S)-2-(Ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-amide is obtained in the form of an oil, which can be purified by flash-chromatography on silica gel using a mixture of ethyl acetate/n-hexane=3:1.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[OH:1][CH:2]([CH2:3][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]1)[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: O=C1c2ccccc2-c2c(OC[C@@H]3CO3)cccc21
Product: O=C1c2ccccc2-c2c(OCC(O)CNCC3CCN(CCC(F)(F)F)CC3)cccc21
Yield: 58.5 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9-fluorenone (0.087 g, 0.34 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.126 g, 0.6 mmol) of according to the procedure used for Example 2 to give 0.092 g of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([CH2:22][OH:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([CH:22]=[O:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc(CO)c1-c1ccc(OC)cc1OCOC
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCn1cnc(C=O)c1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
To a solution 1-n-butyl-4-hydroxymethyl-5-(2-methoxymethoxy-4-methoxyphenyl)-1H-imidazole (0.05 g, 0.16 mmol) in toluene (5 mL) was added manganese oxide (0.04 g, 0.47 mmol). The mixture was stirred for 5 h at room temperature. The mixture was filtered and the filtrate was evaporated to dryness. Flash column chromatography (1:4 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.05 g, 94%). 1H NMR (250 MHz, CDCl3)δ 9.65 (s, 1H), 7.58 (s, 1H), 7.13 (d, 1H), 6.80 (d, 1H), 6.65 (dd, 1H), 5.05 (s, 2H), 3.90 (s, 3H) 3.80 (t, 2H), 3.35 (s, 3H), 1.55 (quintet, 2H), 1.25 (quintet, 2H), 0.83 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Step G (75 mg, 0.21 mmol) and NMM (42 mg, 0.42 mmol) in DCM (3 mL) was added methanesulfonyl chloride (36 mg, 0.38 mmol). Then the mixture was stirred at room temperature for 3 h, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3/1) to afford the title compound as colorless oil. LC/MS m/z=435.1[M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CO)C[C@H]1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
To a solution of (5)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-1-ol (50 g, 312.5 mmol) and K2CO3 (129.375 g, 937.5 mmol) in dioxane (250 mL) and water (250 mL) at 0° C. was added CbzCl (106.6 g, 625 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The organic solvent was distilled and the residue was dissolved in AcOEt (200 mL). The organic phase was separated and the water was extracted with AcOEt (3×100 ml). The combined organic phase was washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column to give the product (26 g). 1H NMR (CD3OD) 1.1-1.3 (m, 2H), 1.4-1.5 (m, 1H), 1.5-1.7 (m, 3H), 1.8-1.9 (m, 1H), 2.6-2.8 (m, 1H), 3.0-3.1 (t, 1H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 2H), 5.0-5.1 (s, 2H), 7.3-7.4 (m, 5H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[CH3:28][O:29][C:30]([C:32]1([NH2:41])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:31].C(=O)([O-])O.[Na+]>C(Cl)Cl.CC(=O)OCC>[CH3:28][O:29][C:30]([C:32]1([NH:41][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:31]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)Cc2ccccc2C1
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
3-Acetoxy-4-methoxy-benzoic acid (5.00 g, 23.8 mmol) was dissolved in DCM (50 ml). DMF (167 mg, 2.38 mmol) and oxalyl chloride (35.6 ml of a 2 M solution in DCM) were added at room temperature. The mixture was stirred for 20 min, evaporated to dryness in vacuo, the residue redissolved in DCM and evaporated again. The residue was dissolved in DCM and slowly added to a stirred mixture of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (5.42 g, 23.8 mmol), EA and an excess of a saturated aqueous sodium hydrogencarbonate solution. After 90 min the organic layer was separated and washed with a saturated sodium hydrogencarbonate solution, 2 M hydrochloric acid and a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness to give 8.95 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[O:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4].[CH2:30]([NH2:33])[CH2:31][CH3:32].Cl>C(#N)C>[F:28][C:2]([F:29])([F:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15][NH:33][CH2:30][CH2:31][CH3:32])[O:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(=O)(=O)C(F)(F)F)cc3O2)cc1
Reactant: CCCN
Agent: Cl
Solvent: CC#N
Product: CCCNC[C@H]1COc2ccc(S(=O)(=O)C(F)(F)F)cc2O1

Procedure:
Preparation according to Example 2 using [(2R)-7-(trifluoromethylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.39 g, 0.98 mmol), propan-1-amine (1 ml) and ACN (2 ml). Yield: 0.150 g, 45%. The amine was converted to the hydrochloric acid salt and recrystallized from acetonitrile. M.p. 175° C. MS m/z (rel. intensity, 70 eV) 339 (M+, 2) 310 (10), 270 (6), 72 (bp), 70 (6). [α]=+50° (MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5](I)=[CH:4][N:3]=1.[F:11][C@H:12]1[CH2:14][C@H:13]1[C:15]([NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](B1OC(C)(C)C(C)(C)O1)[CH:22]=2)=[O:16]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:23]2[CH:22]=[C:21]3[C:26]([CH:27]=[C:18]([NH:17][C:15]([C@@H:13]4[CH2:14][C@@H:12]4[F:11])=[O:16])[N:19]=[CH:20]3)=[CH:25][CH:24]=2)=[C:6]([CH3:9])[C:7]=1[F:8]
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)OC1(C)C
Reactant: Cc1c(I)cnc(Cl)c1F
Product: Cc1c(-c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)cnc(Cl)c1F

Procedure:
The title compound was prepared following a procedure similar to that described for Example 12, using 2-chloro-3-fluoro-5-iodo-4-methyl-pyridine and (1S,2S)-2-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide, and was carried forward without purification; 0.407 g (98%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12]CC)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.[Li+].[BH4-].[CH2:18]1COC[CH2:19]1>>[CH2:18]([CH:10]([OH:12])[CH2:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:15])=[CH:5][CH:6]=1)[CH3:19]
Reactant: C1CCOC1
Reactant: CCOC(=O)CCc1ccc(Cl)nc1Cl
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)CCc1ccc(Cl)nc1Cl
Temperature: 0 °C

Procedure:
To a solution of ethyl 3-(2,6-dichloropyridin-3-yl)propanoate in THF (12 mL) was added LiBH4 (88 mg, 4.03 mmol). The resultant mixture was stirred at ambient temperature for 2.5 h then was cooled to 0° C. and carefully quenched by addition of saturated NH4Cl(aq) solution. The reaction mixture was diluted with EtOAc and the organic layer washed successively with H2O (1×) and brine (1×). The organic extract was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using a gradient of 0-60% EtOAc/Hexanes as eluent provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 7.58 (1H, d, J=7.92 Hz), 7.25 (1H, d, J=7.80), 3.73 (2H, q, J=5.48 Hz), 2.85 (2H, t, J=7.76 Hz), 1.95˜1.88 (2H, m), 1.42 (1H, m). MS (M+H)+: 205.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=CC(C#N)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C[Mg]Br.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.S(=O)(=O)(O)O.O>O1CCCC1>[O:15]1[C:19]2[CH:2]=[CH:3][C:4]([C:5](=[O:1])[CH3:6])=[CH:9][C:18]=2[CH:17]=[CH:16]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc2occc2c1
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1ccc2occc2c1

Procedure:
To a solution of 5-benzofurancarbonitrile (Japanese Patent Unexamined Publication No. 9-124,631) (1.30 g) in tetrahydrofuran (5 ml) was added 0.87 M methyl magnesium bromide-tetrahydrofuran solution (21 ml), and the resulting mixture was heated under reflux for 4 hours under a nitrogen atmosphere. The reaction mixture was acidified with conc. sulfuric acid and water was added thereto, after which the resulting mixture was subjected to extraction with diethyl ether. The extract solution was washed with water, dried and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography to obtain 1-benzofuran-5-yl-ethanone (1.21 g).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[N:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[NH2:30])=[CH:25][C:24]=2[CH3:32])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][NH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Li+]>CO.C1COCC1>[N:22]1[NH:21][N:20]=[N:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[NH2:30])=[CH:25][C:24]=3[CH3:32])[C:7]([CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3nn[nH]n3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To 3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionic acid ethyl ester (26B) (16 mg, 0.035 mmoL) in 1:1 MeOH/THF (1.0 mL) was added aq. 1.0 N lithium hydroxide (2 eq). The reaction mixture was allowed to stir at rt for 16 h. The reaction mixture was poured into 10 mL ice-water solution which was extracted with diethyl ether. The aqueous layer was acidified with aq HCl (2 N) to pH=2, and then was extracted with diethyl ether. The combined organic layers were dried over Na2SO4. The solvent was removed under vacuum to yield the desired target 3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid (26C) (15 mg, 95%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH2:10])[CH2:5][CH:4]1[CH:11]=[CH2:12])=[CH2:2].[CH2:13]([O:15][SiH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:14]>[Pt]>[CH2:13]([O:15][Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH2:2][CH2:1][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])[CH2:5][CH:4]1[CH:11]=[CH2:12])[CH3:14]
Reactant: C=CC1CCC(C=C)C(C=C)C1
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Product: C=CC1CC(CC[Si](OCC)(OCC)OCC)CCC1CC[Si](OCC)(OCC)OCC
Temperature: 110 °C

Procedure:
Into a 5 liter round-bottom flask, equipped with an addition funnel, thermocouple, condenser and a magnetic stir were charged 1,2,4-trivinylcyclohexane (1390 g rams, 8.6 moles) and platinum catalyst (25 ppm of platinum (0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylenes from Aldrich). The mixture was heated to 110° C. and triethoxysilane (1132 grams, 6.9 mole, from Momentive Performance Materials, Inc.) was added drop wise while sparging dry air through the flask. The reaction was exothermic during the addition. The reaction temperature was maintained at approximately 110° C. using a stream of cool air along the side of the flask. After the addition, the reaction was stirred an additional few hours at 110° C. The reaction was monitored using gas chromatography. The products were vacuum distilled at a pressure below 1 torr, to separate out dihydrosilation product, 1,4-bis-[2-(triethoxy-silanyl)-ethyl]-2-vinyl-cyclohexane and its stereoisomers from unreacted trivinylcyclohexane and monohydrosilation product.