Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](I)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20](=[CH2:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>ClCCl.O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]/[C:20](=[CH:28]\[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])/[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)I)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC/C(=C\S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.4 %

Procedure:
To a solution of 4-nitrobenzenesulphonyl iodide (1.49 g, 4.65 mmol) in dichloromethane (6 mL) at room temperature was added tert-butyl 2-(2-methoxyethoxymethyl)acrylate (0.68 g, 3.1 mmol). The mixture was stirred at room temperature for 3.5 hours and triethylamine (0.88 mL, 6.2 mmol) added dropwise. The reaction was stirred for 16 hours, diluted with distilled water (25 mL) and dichloromethane (10 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (5 mL) and the combined organic extracts were washed with 1.0N aqueous hydrochloric acid solution (20 mL), 5% aqueous sodium thiosulphate solution (20 mL) and distilled water (20 mL). The dichloromethane phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a brown oil (1.20 g). The crude product was purified by chromatography on silica by gradient elution with hexane/ethyl acetate mixtures to give, after combination and evaporation of appropriate fractions, the title compound as a yellow oil (0.78 g, 61.9%), Rf =0.33 (silica; hexane/ethyl acetate, 2:1), (MH+ 402.88, 1.07%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH2:15]>C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([NH:15][CH3:14])[CH:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC1CN(C(=O)OC(C)(C)C)CC1O
Temperature: 50 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Dissolve 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.50 g, 8.10 mmol) in methylamine (15 mL, 40% solution in water). Warm to 50° C. and stir in a sealed vessel overnight. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Dry the organics over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-10% methanol (2N NH3)/CH2Cl2 to give 1.87 g (97%) of 3-hydroxy-4-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([C:4]([NH2:6])=[S:5])=[S:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]1[S:3][C:2]2[N:1]=[C:11]([C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH3:7])[S:5][C:4]=2[N:6]=1
Reactant: COc1ccccc1C=O
Reactant: NC(=S)C(N)=S
Product: COc1ccccc1-c1nc2sc(-c3ccccc3OC)nc2s1

Procedure:
2,5-bis(2-methoxyphenyl)thiazolo[5,4-d]thiazole was prepared from dithiooxamide and o-methoxybenzaldehyde. o-Methoxybenzaldehyde was purchased from Aldrich Chemical Company, Milwaukee, Wis.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:12][C:13](=[O:42])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([NH:26][CH2:27][C@H:28]([OH:41])[C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:30]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>>[OH:41][C@H:28]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:30]=1)[CH2:27][NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([OH:43])=[O:2])=[O:42])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from (2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-3-phenyl-propionic acid methyl ester(which was obtained in Example 204) by sodium hydroxide hydrolysis as a pale yellowish solid; mp >160° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.50 (m, 2H), 1.90-2.05 (m, 2H), 2.50-3.50 (m, 7H), 2.95 (s, 3H), 3.69-3.75 (m, 2H), 4.30-4.45 (m, 2H), 4.70-4.75 (m, 1H), 6.83 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.3 Hz, 1H), 7.05-7.30 (m, 7H), 7.63 (d, J=8.8 Hz, 2H), 7.93 (br d, J=6.6 Hz, 1H); MS (ES) m/z: 597.1 (MH+); HRMS Calcd. for C30H35N4O7S(M−H)−: 595.2231. Found: 595.2232.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:28][CH:29]([F:43])[O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH:40]([F:42])[F:41])[CH:34]=O>C1COCC1>[F:41][CH:40]([F:42])[O:39][C:38]1[CH:37]=[CH:36][C:33]([CH:34]=[CH2:1])=[CH:32][C:31]=1[O:30][CH:29]([F:43])[F:28]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (6.7 g, 0.0683 mol) was taken in dry THF (25 mL) and stirred at 0° C. under a nitrogen atmosphere for 15 min. Methyl triphenylphosphonium iodide (27.6 g, 0.0683 mol; see step (ii) above) was then added, followed by 3,4-bis(difluoromethoxy)benzaldehyde (8 g, 0.034 mol; see step (i) above). The reaction mixture was then stirred for 1 h at RT, before being quenched with water. The organic solvents were evaporated under reduced pressure and the aqueous layer extracted with dichloromethane. Evaporation of the solvents followed, by chromatography of the residue over silica gel (using petroleum ether in ethyl acetate as eluent) afforded the sub-title compound as a pale yellow liquid. Yield: 6.5 g
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](NC(=O)OC(C)(C)C)CC2
Yield: 33.5 %

Procedure:
A solution of 10.8 g of (R)-2-tert-butoxycarbonylamino-7-hydroxytetraline (a) in 300 ml of acetone, is heated at reflux under stirring for 6 hours in the presence of 12.4 g of powdered anhydrous potassium carbonate and 15.1 g of ethyl bromoacetate. After filtration, acetone is evaporated under reduce pressure and the residue is taken up with ethyl ether. The solution so obtained is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up with ethyl ether and crystallized from isopropyl ether. Thus, 4.8 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline are obtained; m.p. 113°-115° C., /alpha/=+57.97° (methanol, c=1%).
Reaction SMILES: [OH-].[Na+].C(Cl)Cl.[N+:6]([C:9]1[CH:30]=[CH:29][C:12]([CH2:13][CH:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH:16]=[CH2:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([N:18]([CH2:34][O:33][CH2:31][CH3:32])[C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH:16]=[CH2:17])=[CH:29][CH:30]=1)([O-:8])=[O:7]
Reactant: CCOCCl
Reactant: C=CCC(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCC(Cc1ccc([N+](=O)[O-])cc1)N(COCC)C(=O)OCc1ccccc1
Temperature: 7.5 °C

Procedure:
A mixture of 10 ml of 50% strength aqueous sodium hydroxide solution, 25 ml of methylene chloride and 130 mg (0.4 mmol) of benzyltributylammonium chloride is vigorously stirred at 5-10° C. Benzyl [1-(4-nitrobenzyl)but-3-enyl]carbamate (6.8 g, 20.0 mmol) is added in one portion followed by 2.64 g (28 mmol) of chloromethyl ethyl ether over a period of 2 hours. The mixture is then stirred at room temperature for 1 hour, diluted with ice and water and extracted with methylene chloride. The organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel (hexane/ethyl acetate (10:1)). The title compound is obtained as a colourless oil. TLC: ethyl acetate/hexane (1:3) Rf =0.41. FD-MS: M+ : 398.
Reaction SMILES: ClC1C=CC(CC2CC3N(CC(N)C)C(CC3)C2)=CC=1.C[O:22][C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27](OC)[C:28]=1OC>C(Cl)Cl>[OH:22][CH:23]1[CH2:24][CH:25]2[CH2:26][CH2:27][CH:28]1[C:34](=[O:35])[NH:33]2
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: CC(N)CN1C2CCC1CC(Cc1ccc(Cl)cc1)C2
Solvent: ClCCl
Product: O=C1NC2CCC1C(O)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 2-[3-(4-chlorobenzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-1-methyl-ethylamine in CH2Cl2 was added 3,4,5-trimethoxyphenylisocyanate at −78° C. After the addition, it was allowed to warm up to rt where it was stirred for 4 h. It was then diluted with CH2Cl2. The organic layer was washed with NaCl (sat.) and dried over Na2SO4. The crude product was purified on a silica-gel column with 3% (10% iPr-NH2 in MeOH) in EtOAc to give 55% of Example 4 (m.p. 115–120° C., M+: 502).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=468.1, tR (minutes, Method G)=2.48
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](O)([CH3:9])[CH3:8].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C([O-])(O)=O.[Na+]>CCOCC.O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: Sc1ccccc1Br
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)Sc1ccccc1Br
Temperature: -10 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a 50 mL round-bottomed flask were added a stirbar, water (3.5 mL) and H2SO4 (5.0 mL, 18 M). The flask was then cooled to approximately −10° Celsius and treated with t-BuOH (0.70 mL, 7.5 mmol) followed by 2-bromo-thiophenol (0.60 mL, 5.0 mmol) (drop-wise over three minutes). The resulting mixture was stirred for 24 hours with gradual warming to rt. The reaction mixture was then added to a separatory funnel containing Et2O and sat. NaHCO3. The layers were mixed thoroughly and then separated. The organic layer was washed with 1 N NaOH, dried over MgSO4, filtered and concentrated to dryness. The resulting residue was subjected to FCC gave the title compound (686 mg, 56%). 1H NMR (500 MHz, DMSO-d6) δ 7.75 (dd, J=7.8, 1.4, 1H), 7.68 (dd, J=7.6, 1.6, 1H), 7.43-7.37 (m, 1H), 7.36-7.29 (m, 1H), 1.28 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:22][C:16]1[C:17](=[O:18])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6](=[O:7])(=[O:8])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COCCNS(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 6.1 %

Procedure:
A solution of N-(2-methoxyethyl)-1-phenylmethanesulfonamide (3.5 g, 14.5 mmol) and diethyl oxalate (2.33 g, 16.0 mmol) in dry DMF was cooled in an ice-bath. Potassium tert-butoxide (2.17 g, 18.4 mmol) was added and after 5 mins the ice-bath was removed and the reaction was stirred at rt for 22 h. 2M HCl (45 mL) was added to the mixture and the acidic solution was extracted 3 times with dichloromethane. The combined organic layers were washed 4 times with water, dried through a phase separator and evaporated. The residue was purified by preparative HPLC [0.1M NH4OAc/MeCN, (9:1 to 1:9)] to give the title compound (0.250 g, 6%) as a solid; 1H NMR (500 MHz, CD3OD): δ 7.90-7.94 (m, 2H), 7.28-7.33 (m, 2H), 7.10-7.15 (m, 1H), 3.79 (t, 2H), 3.68 (t, 2H), 3.34 (s, 3H); Mass Spectrum: M−H+ 282.
Reaction SMILES: [OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C1(C)C=CC=CC=1.CN1CCCC1=O>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:28](=[O:29])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 14.85 g of 5-chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}amide (MW=409.89; 1 eq.) in 145 mL toluene and 22 mL N-methylpyrrolidone were added 7.13 g (MW=162.15; 1.2 eq.) of 1,1′-carbonyldiimidazol. The reaction mixture was heated to 80° C. After stirring for 30 minutes the mixture was heated to 110° C. and stirred at this temperature for 2 hours. Then the mixture was cooled to 22° C. After stirring for 1 hour at ambient temperature the product was isolated by filtration and washed with 60 mL of toluene and 60 mL of water. The wet product was dried at 30° C. in vacuo to yield 15.99 g (MW=435.89; 1.013 eq.) of the title compound (90% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O)[C:6](=O)[CH3:7])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:7])=[O:19])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1)C(C)=O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)c1C

Procedure:
The title compound was prepared from 2-[2-(4-chloro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester (from Example 35(a)) and aniline under conditions analogous to Example 35(b). MS-(+)-ion: M+1=340.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])[CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12
Yield: 88.9 %

Procedure:
0.50 g (12.6 mmol) of 60% strength sodium hydride in paraffin oil is introduced under argon into 20 ml of THF at room temperature. A solution of 2.0 g (8.40 mmol) of 5-bromo-3-isopropyl-1H-indole (Example X) in 20 ml of THF is added dropwise and the mixture is stirred until evolution of gas can no longer be detected. 2.03 g (13.44 mmol) of tert-butyl(chloro)dimethylsilane are subsequently added dropwise. After a short reaction time a precipitate deposits. The batch is stirred for 3 h at room temperature. It is treated with 200 ml of water. The aqueous phase is extracted twice with ethyl acetate, and the combined org. phases are dried and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent: cyclohexane). 2.63 g (89%) of 5-bromo-1-[tert-butyl(dimethyl)silyl]-3-isopropyl-1H-indole are obtained.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[Cl:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36](=O)[CH2:37]Br>>[Cl:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]1[N:1]=[C:2]([N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)[S:3][CH:37]=1
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(-c3ccccc3Cl)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorophenacyl bromide.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>C(#N)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1
Reactant: COCCCBr
Reactant: Cc1cc(CCN)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COCCCNCCc1ccc(C#N)c(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A mixture of 500 mg 4-(2-Amino-ethyl)-2-methyl-benzonitrile trifluoro acetate and 756 mg potassium carbonate were stirred in 10 ml acetonitrile at 80° C. for fifteen minutes. Then 279 mg 1-bromo-3-methoxypropane, dissolved in 5 ml acetonitrile, were added dropwise at 80° C. The reaction mixture was stirred under micro wave irradiation at 120° C. for one hour. The cooled reaction mixture was filtered through a pad of celite to remove the salt. Then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 268 mg 4-[2-(3-Methoxy-propylamino)-ethyl]-2-methyl-benzonitrile as its trifluoroacetate salt.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:2]#[CH:3].Br[C:15]1[C:16]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C>O1CCOCC1.[Pd](Cl)Cl.C(#N)C1C=CC=CC=1.C(#N)C1C=CC=CC=1.[Cu]I>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][N:4]1[CH2:1][C:2]#[C:3][C:15]1[C:16]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCN1CCc2ccccc2C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCc2ccccc2C1
Yield: 46.5 %

Procedure:
2-Prop-2-ynyl-1,2,3,4-tetrahydro-isoquinoline (0.72 mmol), 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.86 mmol), Bis(benzonitrile)-palladium(II)chloride (0.02 mmol), copper (I) iodide (0.015 mmol), tri-tert-butylphosphine (0.04 mmol) and diisopropyl amine (0.86 mmol) in dioxane (4 ml) is stirred at room temperature for 2.5 h. After filtration, the reaction mixture is treated with saturated ammonium chloride. The mixture is extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a column of silica gel, which is eluted with following solvents: n-hexane:AcOEt=1:1 (v/v) and n-hexane:AcOEt=1:5 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 46.5%, Rf=0.31 (n-hexane:AcOEt=1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(O)ccc2c1
Product: COc1ccc2nc(Cl)ccc2c1
Yield: 86 %

Procedure:
A solution of 6-methoxyquinolin-2-ol (400 mg, 2.29 mmol) in POCl3 (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), the organic layer was washed with saturated NaHCO3 (30 mL×2), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column (PE/EtOAc=10/1) to give 2-chloro-6-methoxyquinoline (380 mg, yield 86%) as a solid. 1H NMR (CDCl3 400 MHz): δ 7.92 (d, J=8.4 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.00 (d, J=2.4 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH:11]=[O:12])[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][OH:12])[C:7]([C:13]([F:14])([F:16])[F:15])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 39.9 g (156.9 mmoles) of 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 300 ml of methanol was cooled to 0° C. Thereto was gradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 37.7 g (yield: 93.6%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:21]1
Reactant: Oc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1cccc(-c2c[nH]cn2)c1

Procedure:
A solution of 0.170 g of 3-(1-trityl-1H-imidazol-4-yl)phenol, 4.5 ml of methanol, 1.5 ml of chloroform and 1.5 ml of 2N HCl is stirred at 55° C. for 2 hours. After cooling, the reaction mixture is admixed with 35 ml of aqueous saturated sodium hydrogencarbonate solution and extracted twice with 75 ml of dichloromethane. The combined organic phases are washed with 35 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.14 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=2.08.