Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-]#N.[CH3:11][N:12]([S+](N(C)C)N(C)C)C>C(#N)C>[CH2:2]([C:11]#[N:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)[S+](N(C)C)N(C)C
Agent: [C-]#N
Solvent: CC#N
Product: N#CCc1ccccc1
Yield: 95 %

Procedure:
A 1.71-g (10 mmole) sample of α-bromotoluene was injected into a solution of 1.90 g (10 mmole) of tris(dimethylamino)sulfonium cyanide in 2.4 ml (1.9 g) acetonitrile, and the mixture was shaken. The mixture became warm. After cooling, analysis by gas chromatography showed that all of the α-bromotoluene had been consumed, benzyl cyanide was formed in 95% yield, and benzyl isocyanide was formed in 5% yield. Crystals of tris(dimethylamino)sulfonium bromide separated from the reaction mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:28](=[O:29])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCCS(C)(=O)=O
Product: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Yield: 10 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 17 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). A second chromatography (preparative HPLC (Phenomenex Gemini® column), gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2)) gave the desired product as an off-white foam (10%). MS (ESI): m/z=566.10 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:15][C@H:16]([C:24](O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[NH:15][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:25])([CH3:14])([CH3:12])[CH3:13]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (75 mmol) and Boc-L-phenylalanine (38 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 144 hour reaction time) and the product used without further purification. Yield 12.2 g, 96%; HPLC (60/40) 3.45 minutes (97%).
Reaction SMILES: [Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[O:11]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH:21]([OH:24])[C:22]#[N:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:24][CH:21]([C:22]#[N:23])[C:20]1[CH:25]=[CH:26][CH:27]=[C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(Cl)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(Cl)Cl
Temperature: 10 °C
Reaction time: 16 h

Procedure:
2,2-Dichloro-3,3-dimethylcyclopropanoyl chloride (2.69g) was dissolved in dry toluene (50ml) and this solution was added dropwise to a stirred solution of 3-phenoxymandelonitrile (3.0g) and triethylamine (2.69g) in dry toluene (50ml) maintained at 10°C. The mixture was then stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was washed in turn with 5 % sulphuric acid, saturated sodium bicarbonate and water, and then dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel eluting in turn with toluene, 1 : 1 toluene/hexane and toluene. The required product was obtained as an oil nD20 1.5630.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pt]>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH3:7])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: Cc1ccc(C(F)(F)F)cc1
Reaction time: 10 h
Yield: 77.7 %

Procedure:
4-Trifluoromethylbenzaldehyde (20.0 g) was dissolved in acetic acid (100 ml) and treated with hydrogen in the presence of platinum (0.5 g) at ambient temperature and pressure for 10 hours. The solution was filtered, poured into water (400 ml), basified by addition of aqueous sodium hydroxide solution (2 M), extracted with ether (3×100 ml). The combined extracts were washed with water (2×100 ml), dried over anhydrous magnesium sulphate, evaporated to dryness. The residue was distilled to give 4-trifluoromethyltoluene (14.3 g) b.p. 131°-132° C. as a colourless mobil liquid.
Reaction SMILES: [Br:1]Br.[CH:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1.S([O-])(O)=O.[Na+]>>[Br:1][C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1
Reactant: C1CC2CC(C1)C1CCC2C1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Product: BrC12CCCC(C1)C1CCC2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To 20 ml (387 m mole) of liquid bromine was added 10 g (48 m mole) of tricyclo[4.3.1.12,5 ]undecane and the resulting mixture was stirred at room temperature for 17 hours. To a cooled saturated sodium hydrogen sulfite solution was added dropwise with stirring the reaction mixture to remove excess bromine. This aqueous solution was extracted twice with a portion of 200 ml of carbon tetrachloride, and the extract was dried over magnesium sulfate. The carbon tetrachloride was evaporated to obtain 19 g of the residue, which was distilled under reduced pressure, and the fraction having a boiling point of 96° to 98° C./2 mmHg was collected. This was a colorless crystalline material having a melting point of 57.5° to 58.5° C.
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[C:14]([C:17]#[N:18])[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[F:19].C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:17]([C:14]1[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]([F:19])=[C:2]([C:25]([O:27][CH2:28][CH3:29])=[CH2:26])[C:15]=1[CH3:16])#[N:18]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Under nitrogen atmosphere, bis(triphenylphosphine)palladium chloride (435 mg, 620 μmol) was added to a toluene (125 ml) solution of 6-bromo-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-127) (4.04 g, 12.4 mmol), tributyl(1-ethoxyvinyl)tin (5.37 g, 14.9 mmol) and 2,6-di-tert-butyl-p-cresol (about 20 grains), and heated under reflux for 20 hours. After cooling, the solvent was evaporated away under reduced pressure, then n-hexane was added to the resulting residue and stirred at room temperature for 1 hour. Next, the precipitated solid was collected by filtration and subjected to silica gel column chromatography, and the eluate with n-hexane/ethyl acetate (1:1, v/v) gave 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (3.20 g, 81%) as a yellow solid. The fraction containing impurities was recovered and purified in the same manner, and 3.57 g (91%) of 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide was obtained in total. The analytical data are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:47][N:48]([CH3:52])[C:49](Cl)=[O:50].[H-].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([O:45][C:49](=[O:50])[N:48]([CH3:52])[CH3:47])([CH3:46])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [H-]
Agent: [K+]
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 30a, 335 mg of 1-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2-methyl-propan-2-ol (from example 128a) and 0.5 g of N,N-dimethylcarbamoylchloride in the presence of 137 mg of potassium hydride are used to afford the title compound as a yellow oil. Rt=5.62.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=[O:4].[Na].Cl[C:10]([CH3:20])=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=O.[Li+].[OH-]>C(O)C>[CH3:20][C:10]1[S:1][C:2]([C:3]([OH:5])=[O:4])=[CH:12][C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CS
Reactant: CC(Cl)=C(C=O)c1ccccc1
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Ethyl 2-mercaptoacetate (5.92 g, 49.3 mmol) is added to a freshly prepared solution of sodium (1.2 g, 50 mmol) in ethanol (50 mL). To this solution 3-chloro-2-phenyl-but-2-enal (8.90 g, 49.3 mmol) is added and the mixture is stirred at rt for 16 h, then at 70° C. for 2 h. A 2 N aq. solution of LiOH (30 mL) is added and stirring is continued at 70° C. for 2 h. The ethanol is removed in vacuo, the remaining mixture is diluted with water and extracted with DCM. The aq. phase is acidified with aq. HCl and extracted with diethyl ether. The solvent of the ether phase is evaporated, the residue is suspended in acetonitrile, filtered and washed with additional acetonitrile and dried to give 5-methyl-4-phenyl-thiophene-2-carboxylic acid (4.45 g) as a yellow powder, LC-MS: tR=0.92 min, [M+1+MeCN]+=260.13; 1H NMR (CDCl3): δ 7.84 (s, 1H), 7.46-7.33 (m, 5H), 2.55 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][S:35]([NH:34][C:30]1[CH:31]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)[CH:33]=[CH:28][CH:29]=1)(=[O:37])=[O:36]
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 90 °C
Yield: 85.9 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (235 mg, 0.60 mmol, prepared in example 2) and N-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (213 mg, 0.72 mmol) were dissolved in 25 mL of n-propanol and 25 mg (0.18 mmol)of potassium carbonate in 5 mL of water added. A catalytic amount of palladium acetate is added (7 mg) and the mixture refluxed at 90° C. for 4 hours. The reaction is worked up as in preparation 6. Purification by silica chromatography using a Chromatotron® was achieved eluting with 90:10 methylene chloride:ethyl acetate to afford 225 mg (86%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:22]([O:24]C)=[O:23].[Li+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1c(Cl)ccc2c(Nc3cccc(C(F)(F)F)c3)noc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1c(Cl)ccc2c(Nc3cccc(C(F)(F)F)c3)noc12
Temperature: 50 °C

Procedure:
To a solution of methyl 6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxylate (1.0 g, 2.8 mmol) in dioxane (30 mL) was added a 1N solution of LiOH, monohydrate (0.59 g, 14 mmol). The reaction mixture was heated at 50° C. for 2 h. The solvent was removed and to the aqueous solution was added 2N HCl until pH 4. The precipitate formed was collected by filtration, washed with water (5 mL) and dried to give 6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxylic acid as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([N+:25]([O-:27])=[O:26])[CH:15]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:21]([C:17]2[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=2[N+:25]([O-:27])=[O:26])(=[O:22])=[O:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 14.2 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloro-quinolin-8-ylamine (Intermediate 27) (400 mg, 2.2 mmol), 4,5-difluoro-2-nitro-benzenesulfonyl chloride (Intermediate 219) (750 mg, 2.9 mmol), DMAP (cat.) and pyridine (5 ml) and DCM (5 ml) gave the title compound (125 mg, 14%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH3:18])[C:5](=[O:17])[CH:6](C(=O)C)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8].Cl.C(OCC)C>C(O)C>[CH3:18][CH:4]([CH3:3])[C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8]
Reactant: CCCCOC(=O)C(C(C)=O)C(=O)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCCCOC(=O)CC(=O)C(C)C
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a solution of 42 g of NaOH in 50 ml of ethanol was added 0.1 mol of butyl 4-methyl-2-acetyl-3-oxo-valerate, and the reaction mixture was stirred for 10 hrs. Then to the reaction was added 50 ml of crushed ice, and the mixture was neutralized with hydrochloric acid. Diethyl ether was used to extract product, and the collected organic layer was dried over anhydrous sodium sulfate. The product was obtained by distillation under reduced vacuum.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([NH2:11])=O)[CH2:5][CH2:4]1.[BH4-].[Na+].II.CO>C1COCC1>[F:1][C:2]([F:12])([F:13])[CH:3]1[CH2:4][CH2:5][CH:6]([CH2:9][NH2:11])[CH2:7][CH2:8]1
Reactant: NC(=O)C1CCC(C(F)(F)F)CC1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NCC1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Yield: 9.7 %

Procedure:
At 0° C. a solution of 4-trifluoromethylcyclohexanecarboxylic acid amide (1.38 g, 7.07 mmol) in THF (20 ml) was added to a suspension of sodium borohydride (0.64 g, 16.97 mmol) in THF (20 ml). A solution of iodine (1.79 g, 7.07 mmol) in THF (20 ml) was added dropwise. The reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (40 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in tert-butyl methyl ether (100 ml) and a 20% aqueous solution of sodium hydroxide. The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×70 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using DCM/methanol/25% aqueous ammonia (first 100:10:1; then 50:10:1) as eluent, to give 124 mg of ((4-trifluoromethylcyclohexyl)methyl)amine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]([OH:23])[CH3:22])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>ClCCl.O=[Mn]=O>[C:21]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]([C:11]1[C:2]([Cl:1])=[N:3][C:4]3[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20]2)(=[O:23])[CH3:22]
Reactant: CC(O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-chloro-3-quinolinyl)-5-(1-hydroxyethyl)-1H-indole-1-carboxylate (8-2, 840 mg, 1.99 mmol, 1 equiv) and MnO2 (863 mg, 9.93 mmol, 5.00 equiv) in dichloromethane (30 mL) was heated at reflux for 1 hour. Additional MnO2 (500 mg, 5.75 mmol, 2.89 equiv) was added and heating was continued for 1 hour. The catalyst was filtered and washed with dichloromethane (100 mL). The combined filtrate was concentrated to give tert-butyl 5-acetyl-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (8-3) as a white foam. 1H NMR (500 MHz, CDCl3) δ 8.38 (d, 1H, J=8.8 Hz), 8.27 (d, 1H, J=0.7 Hz), 8.21 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 8.04 (dd, 1H, J=8.8, 1.2 Hz), 7.89 (d, 1H, J=8.1 Hz), 7.80 (br t, 1H, J=7.6 Hz), 7.63 (br t, 1H, J=7.5 Hz), 6.76 (s, 1H), 2.70 (s, 3H), 1.27 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[Li]CCCC.[B:22]([O:31]C(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[C:13]([S:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][C:7]=1[O:23][B:22]([OH:31])[OH:27])(=[O:12])=[O:11])([CH3:15])([CH3:14])[CH3:16]
Reactant: CCc1ccc(NS(=O)(=O)C(C)(C)C)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(NS(=O)(=O)C(C)(C)C)c(OB(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-ethylphenyl-t-butylsulfonamide (6.44 g, 26.7 mmoL) in anhydrous THF (60 mL) cooled to -20° C. under N2 was added 2.5M n-BuLi solution (27 mL, 2.5 equiv). The mixture was warmed to rt and stirred for 2 h. To the mixture, containing the bright orange dianion at 0° C., was added B(OiPr)3 (9.3 mL, 1.5 equiv). The reaction was allowed to warm to rt and stirred overnight. The next day 2N HCl (3 mL) was added and the mixture was stirred for 1 h. The solvent was removed under reduced pressure and the residue was extracted with EtOAc. The organic was washed with 2N HCl, H2O and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. Rf=0.5 (1:1 EtOAc/Hex). The material was used in subsequent steps without further purification.
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)C.[C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH3:15].[Li]>>[C:18]([O:17][C:14](=[O:16])[CH2:15][C:4]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)=[O:13])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ccnc(C#N)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from 2-cyano-isonicotinic acid ethyl ester [CAS-No. 58481-14-4] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light brown solid (7.70 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:32][CH3:33])=[CH:21]/[CH2:22][C:23]([CH3:31])([CH3:30])[C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])[CH:16]=1)(C(C)(C)C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][C:36]=1[CH2:37][OH:38])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:32][CH3:33])=[CH:21]/[CH2:22][C:23]([CH3:31])([CH3:30])[C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])[CH:16]=1
Reactant: CC/C(=C\CC(C)(C)C(O)(CC)CC)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC/C(=C\CC(C)(C)C(O)(CC)CC)c1csc(COc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to that of Example 6(l), by reaction of 310 mg (0.46 mmol) of (E)-7-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-3-ethyl-4,4-dimethylnon-6-en-3-ol with 1.1 mL (1.1 mmol) of 1.0 M tetrabutylammonium bromide, the desired product is obtained in the form of a colourless oil (m=200 mg; Y=98%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a mixture of methyl 2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.55 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (2.5 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify 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 to give crystals (0.45 g, 87%) of 2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 166-167° C.
Reaction SMILES: Br[CH2:2][F:3].[NH+]1C=CC=CC=1.[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@@H:11]1[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH2:23]1)=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@@H:11]1[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:2][F:3])[CH:29]=2)[CH2:23]1)=[O:21]
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(O)c2)C1
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(OCF)c2)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Bromofluoromethane-pyridinium adduct (excess) was condensed in a vial. (R)-2,3-Dihydro-benzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-yl]-methanone (1.84 mmol, 0.623 g) and K2CO3 (3.67 mmol, 0.507 mmol) were added and the tube was sealed. Acetonitril (5 ml) was added. The reaction was stirred at 120° C. for 60 min. After cooling, the mixture was evaporated to dryness, taken up in DCM and washed with water. The organic phase was evaporated to dryness. 0.680 g of the title compound was obtained.