Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1.[OH-].[K+]>[Cu]>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: COc1ccc(O)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
4-Bromonitrobenzene (4.0 g), hydroquinone monomethyl ether (3.1 g), potassium hydroxide (1.5 g) and copper powder (0.1 g) were mixed and the reaction was carried out at 160° C. to 200° C. for 3 hours. After cooling to room temperature, the reaction mixture was extracted with benzene (100 ml), and the extract was washed with 1 N sodium hydroxide, water, and saturated aqueous sodium chloride After drying over magnesium sulfate, the solvent was evaporated under a reduced pressure and the residue obtained was purified by medium pressure column chromatography using silica gel, to obtain 4-(4-nitrophenoxy)phenol methyl ether (1.5 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=2)=[CH:15][C:14]=1[C:30]1[CH:39]=[CH:38][C:37]2[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[C:32]=2[CH:31]=1>C(C(C)=O)C>[Br:1][CH2:2][CH2:3][CH2:4][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=2)=[CH:15][C:14]=1[C:30]1[CH:39]=[CH:38][C:37]2[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[C:32]=2[CH:31]=1
Reactant: BrCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
320 μl (3.14 mmol) of 1,3-dibromopropane and 440 mg (3.18 mmol) of potassium carbonate are added to a solution of 900 mg (2.1 mmol, 1 eq) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 30 ml of methyl ethyl ketone. The reaction mixture is stirred overnight at room temperature and then for 1 day at reflux. The medium is cooled to room temperature and then filtered. The filtrate is evaporated and the residue is purified by chromatography on silica gel (eluent: 90/10 heptane/ethyl acetate). 640 mg of ethyl 4′-(3-bromopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=55%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH:7]([OH:11])[CH2:8][CH:9]=[CH2:10])[CH3:4].Br[CH2:14][C:15]([CH3:17])=[CH2:16]>C1COCC1>[CH2:3]([O:5][C:6](=[O:12])[CH:7]([O:11][CH2:16][C:15]([CH3:17])=[CH2:14])[CH2:8][CH:9]=[CH2:10])[CH3:4]
Reactant: C=C(C)CBr
Reactant: C=CCC(O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(=C)C)C(=O)OCC
Temperature: 0 °C
Yield: 65.7 %

Procedure:
To a cold (0° C.) stirred suspension of NaH (55% dispersion in oil, 227.9 mg, 5.2 mmol, 1.3 eq) in THF (20 mL) was added drop wise a solution of 2-hydroxy-pent-4-enoic acid ethyl ester (0.576 g, 4.0 mmol) in THF (20 mL) and stirred for 1 h. The reaction mixture was then treated with 3-bromo-2-methylpropene (0.81 g, 6.0 mmol, 0.61 mL), slowly warmed up to rt, and stirred for 1 h. It was carefully quenched with saturated NH4Cl solution. Reaction mixture was extracted with EtOAc (3×20 mL) organic solution was washed with brine, dried (Na2SO4), concentrated. Purification of the residue on silica gel column chromatography using 5% EtOAc-Hexane furnished 2-(2-methyl-allyloxy)-pent-4-enoic acid ethyl ester (0.521 g, 66%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13](O)=[O:14].S(Cl)([Cl:19])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13]([Cl:19])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl

Procedure:
A mixture consisting of 61 g. (0.20 mole) chloroglyoxylic acid (2,4,6-trichlorophenyl)hydrazone, 200 ml. carbon tetrachloride, and 100 ml. thionyl chloride was heated at the reflux temperature for 6 1/2 hrs. The carbon tetrachloride and thionyl chloride were removed by evaporation under reduced pressure and 50° C. to give 64 g. of an oil. The oil was extracted with technical hexane and the insoluble starting material was removed by filtration. The technical hexane was removed by evaporation under reduced pressure to give chloroglyoxyloyl chloride (2,4,6-trichlorophenyl) hydrazone.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([S:12][C:13]1[S:17][C:16]([NH:18][C:19]([N:21]2[C:37]3[C:32](=[CH:33][C:34]([Cl:38])=[CH:35][CH:36]=3)[C:23]3([CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24]3)[CH2:22]2)=[O:20])=[N:15][CH:14]=1)[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:38][C:34]1[CH:33]=[C:32]2[C:23]3([CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24]3)[CH2:22][N:21]([C:19](=[O:20])[NH:18][C:16]3[S:17][C:13]([S:12][CH:10]([CH3:11])[CH2:9][OH:8])=[CH:14][N:15]=3)[C:37]2=[CH:36][CH:35]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SC(C)CO[Si](C)(C)C(C)(C)C)s1)c1ccc(Cl)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SC(C)CO)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 11.3 h
Yield: 73.1 %

Procedure:
Methyl 1-((5-((1-((t-butyldimethylsilyl)oxy)propan-2-yl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (200 mg, 0.34 mmol) was dissolved in tetrahydrofuran (10 mL). Thereafter, a tetrahydrofuran solution (0.2 mL, 1.7 mmol) of tetrabutylammonium fluoride (1 mol/mL) was added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 11.3 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the captioned compound (0.12 g, 72%) in the form of a white amorphous product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:35])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27]CC2C=CC=CC=2)[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO>[Si:1]([O:8][CH2:9][C@H:10]([CH3:35])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CO
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-(phenylmethyl)oxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.8 g, 3.64 mmol) was dissolved in methanol (50 mL) and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (0.2 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, and the filtrate concentrated in vacuo to give the desired compound (1.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([Mg]Br)#[C:11][CH3:12].C1COCC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[C:10]#[C:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To an ice cold solution of 4-bromobenzaldehyde (1.3 g, 7 mmol) 0.5 M solution of propynyl magnesium bromide in THF (15 ml, 7.5 mmol) was added under N2. The mixture was stirred for 10 min, quenched with saturated NH4Cl solution and diluted to 50 ml with EtOAc. The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was dissolved in 1,4-dioxane (25 ml). To it MnO2 (2 g) was added and the resulting suspension was stirred for 4 h at reflux. The mixture was filtered through Celite pad and the filtrate was evaporated to dryness and dried in vacuo to give the title compound (1.29 g, 83%) as a pale solid. 1H-NMR (CDCl3) 7.97 (d, 2H, J=9 Hz); 7.61 (d, 2H, J=9 Hz); 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:9]2)=[CH:4][CH:3]=1.CO[C:37](=O)[C:38]1[CH:43]=[C:42]([S:44](=[O:51])(=[O:50])[NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([Cl:52])=[CH:40][C:39]=1[O:53][CH2:54][CH3:55].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[NH:11][C:37]([C:38]3[C:39]([O:53][CH2:54][CH3:55])=[CH:40][C:41]([Cl:52])=[C:42]([S:44]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:51])=[O:50])[CH:43]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C(=O)OC
Agent: C[Al](C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) was reacted with 5-tert-butylsulfamoyl-4-chloro-2-ethoxybenzoic acid methyl ester (example 43) in the presence of trimethylaluminum to give the title compound. HR-MS (ES, m/z) calculated for C29H33N3O3SCl3 [(M+H)+] 608.1303, observed 608.1300.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:16])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1.Cl.[CH3:18][OH:19]>C(Cl)(Cl)Cl>[CH3:1][N:2]=[C:3]([NH2:16])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:15])[O:19][CH3:18])[N:6]=1
Reactant: CN=C(N)Nc1cnn(CCCCC#N)n1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN=C(N)Nc1cnn(CCCCC(=N)OC)n1

Procedure:
A solution of 5-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeronitrile (0.8 g.) in a mixture of chloroform (15 ml.) and MeOH (5 ml.) was saturated at 0° with hydrogen chloride gas and the mixture maintained at 0° for 3 days. The mixture was evaporated to dryness and the residue basified with cold sodium carbonate solution and extracted witn chloroform. The extract was dried and evaporated to give methyl 5-[4-(2-methylguanidino)1,2,3-triazol-2-yl]valerimidate as a yellow oil (1.07 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[CH:27]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1)c1ccc(Cl)cc1C

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 with the intermediate C and the 3-chloroaniline. The reaction mixture was diluted in DCM/water and the phases were separated. The organic phase was dried (Na2SO4) and concentrated. The product was purified by flash chromatography (heptane/EtOAc, 9:1) to give the title compound. tR: 1.47 min (LC-MS 2); ESI-MS: 524.0/526.0/528.2 [M+H]+ (LC-MS 2).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)C=CC=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][C:30]=1[Br:31])[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:20]3[CH:28]=[CH:29][C:30]([Br:31])=[C:18]([Br:17])[CH:19]=3)[CH2:27][CH2:26]2)=[O:16])=[N:11][CH:12]=1
Reactant: O=C(Nc1ccncn1)Oc1ccccc1
Reactant: Brc1ccc(CN2CCNCC2)cc1Br
Product: O=C(Nc1ccncn1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1

Procedure:
The title compound was prepared from pyrimidin-4-yl-carbamic acid phenyl ester and 1-(3,4-dibromo-benzyl)-piperazine in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.40 (s, 1H), 8.10-7.80 (m, 1H), 7.70-7.50 (m, 1H), 7.58-7.45 (m, 1H), 7.14-7.10 (m, 1H), 6.55-6.40 (m, 1H), 3.40 (s, 2H), 2.87 (t, J=4.8 Hz, 4H), 2.38 (t, J=4.8 Hz, 4H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:20][CH2:19][NH:18][NH:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>ClCCl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:40]([NH:39][CH2:37][CH3:38])=[O:41])[NH:18][CH2:19][CH2:20]2)=[CH:26][CH:25]=1
Reactant: CCN=C=O
Reactant: Fc1ccc(C(CCCN2CCNNCC2)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-[4,4-bis(4-fluorophenyl)butyl]hexahydro-1H-1,2,5-triazepine dihydrochloride (3.25 g, prepared as in example 13), N,N-diisopropylethylamine (3.38 ml) in dry dichloromethane (10 ml) at 5° under nitrogen was added ethyl isocyanate (0.62 ml) in dichloromethane (10 ml) and the solution was stirred at room temperature overnight. After extraction of the mixture with water, the dichloromethane solution was dried (Na2SO4) and evaporated to an oil. The crude product was chromatographed on a column of silica gel prepacked in dichloromethane. Successive elution with ethyl acetate-dichloromethane (4:1) and ethanol-ethyl acetate-dichloromethane (1:4:5) allowed a separation of a major component from impurities. The hydrobromide salt of the titled compound was formed from the material in 2-propanol and was recrystallized from 2-propanol-ethyl acetate; wt. 2.18 g (49%), mp=130°-134° dec.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]#[C:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([Cl:24])(=[O:23])N>>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]#[C:19][CH3:20])[C:21]([Cl:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cl
Reactant: CC#COCCOCCOCCNCc1ccccc1
Product: CC#COCCOCCOCCN(Cc1ccccc1)C(=O)Cl

Procedure:
N-Benzyl-2-(2-(2-(propynyloxy)ethoxy)ethoxy)ethyl aminocarbonyl chloride was prepared from amine 27 (20 mg, 0.072 mmol) following General Procedure 1. The crude carbamoyl chloride was used directly for the next step.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:17])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CSc1ccc(CCl)cc1C(F)(F)F
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 4-(methylthio)-3-(trifluoromethyl)benzyl alcohol (3.00 g, 13.5 mmol) in toluene (15 mL) was added thionyl chloride (1.18 mL, 16.2 mmol) at room temperature, and the resulting mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1), and crystallized from hexane to give the title compound (2.54 g, yield 78%) as colorless crystals.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)([O-:16])=[O:15].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCc1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution of N-Boc-ethanolamine (477 mg) in tetrahydrofuran (10 mL), sodium hydride (118 mg, 60 wt %) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour under a nitrogen atmosphere. To the reaction mixture, 2-nitrobenzyl bromide (500 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour, and then further stirred at room temperature for 4 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 80 to 70% hexane in ethyl acetate) to obtain oily tert-butyl (2-((2-nitrobenzyl)oxy)ethyl)carbamate (C11, 154 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O>S(Cl)(Cl)=O.ClCCl>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: CO
Reactant: O=C(O)c1ccnc(Cl)c1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
2-Chloro-3-fluoroisonicotinic acid (3.30 g, 18.8 mmol) was suspended in thionyl chloride (40 ml) and heated under reflux for 2.5 h. The solvent was evaporated and the residue dried by means of azeotropic removal of water with toluene (100 ml) to afford a pale yellow oil. The oil was dissolved in dichloromethane (20 ml) and cooled to 0° C. before methanol (2.42 g, 75.3 mmol) was added dropwise to the solution over 15 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The solvent was evaporated and the mixture partitioned between water (75 ml) and dichloromethane (100 ml). The aqueous phase was extracted further with dichloromethane (100 ml), the organic layers were combined, washed with brine (75 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give 2-chloro-3-fluoroisonicotinic acid methyl ester (3.32 g, 93%) as a pale yellow solid: δH (360 MHz, CDCl3) 3.99 (3H, s), 7.70 (1H, dd, J 5 and 5), 8.31 (1H, d, J 5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(O)C.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:19][CH2:20][CH2:21][O:22]4)[CH2:17][CH2:16]3)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Fc1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1F

Procedure:
A solution of 4.9 g of 8-[4-(3,4-difluorophenyl)-3-cyclohexenyl]-1.4-dioxaspiro[4.5]decane in 670 ml of ethanol was hydrogenated with 1.0 g Raney nickel at 50° C. under normal pressure until the hydrogen uptake came to a standstill. The reaction mixture was filtered and the filtrate was concentrated. Threefold recrystallization of the obtained crude product (5.0 g) from diethyl ether/hexane yielded 2.52 g of 8-[trans-4-(3,4-difluorophenyl)cyclohexyl]-1, 4-dioxaspiro[4.5]decane. The mother liquors were evaporated. Isomerization of the residue (2.2 g) under inert gas with 11 ml of dimethyl sulfoxide and 0.344 g of potassium tert. butylate at 100° C. for 7 hours yielded after twofold recrystallization further 0.7 g of 8-[trans-4-(3,4-difluorophenyl)cyclohexyl]-1,4-dioxaspiro-[4.5]-decane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[CH:34]=[CH:33]1.C(N(CC)CC)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([CH:34]=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1ccc2ccc(C(=O)O)cc21
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCCn1ccc2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 12.9 mmol), 1-(3-methoxy-propyl)-1H-indole-6-carboxylic acid (4.22 g, 18.1 mmol), BOPCI (4.6 g, 18.1 mmol) and triethylamine (7.2 mL, 51.7 mmol). TLC, Rf (AcOEt)=0.32.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-t-butoxycarbonylamino-5-trifluoromethylbenzoate (3.80 g; prepared in Reference Example 27.) in methylene chloride (30 ml), trifluoroacetic acid (6 ml) was added. The mixture was stirred for 8 hours at room temperature. The solvent was distilled off azeotropically with toluene three times. To the reaction mixture, an aqueous sodium hydrogencarbonate solution was added to neutralize. The mixture was extracted with ethyl acetate, washed, dried, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt 5:1) to give the title compound (2.35 g) having the following physical data.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3][CH2:2]1.[F:22][C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26]O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(Cl)Cl.CN(C)C=O>[F:22][C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3][CH2:2]1
Reactant: OCCCC(F)(F)F
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CCCC(F)(F)F)CC1
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To a mixture of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol (15.0 mg, 0.0496 mmol) and 4,4,4-trifluorobutanol (9.4 mg, 0.0744 mmol) in methylene chloride (0.3 mL) and N,N-dimethylformamide (0.2 mL) was added resin of tetramethylammonium triacetoxyborohydride (48.4 mg, 0.0992 mmol). The resulting mixture was stirred overnight. The mixture was filtered and concentrated then purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 7 mg (34%) of the desired product. LCMS calculated for C19H24F3N4OS (M+H)+: m/z=413.2. Found: 413.1. 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 7.71-7.60 (m, 2H), 5.21 (s, 1H), 4.72-4.58 (m, 1H), 3.70-3.57 (m, 6H), 3.13 (d, J=9.8 Hz, 2H), 2.89-2.66 (m, 1H), 2.49 (t, J=6.9 Hz, 2H), 2.34-2.18 (m, 2H), 1.96 (s, 1H), 1.86-1.74 (m, 2H), 1.67 (s, 2H) ppm.