Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([O:11]CC)OCC)[O:5][CH:6]=1.C([Li])(CC)C.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>CCOCC>[CH:7]([C:4]1[O:5][C:6]([B:19]([OH:24])[OH:20])=[CH:2][CH:3]=1)=[O:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOC(OCC)c1cc(Br)co1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: O=Cc1ccc(B(O)O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
An amount of 1.0 g (4.1 mmol) of 4-bromo-2-(diethoxymethyl)furan, is dissolved in ether (15 mL) and cooled to −78° C. To this is added 4.3 mL (6.02 mmol) of sec-butyllithium. After stirring at −78° C. for 30 minutes, triisopropyl borate (1.10 mL, 5.01 mmol) is added dropwise. The mixture is stirred at −78° C. for 1.5 hours and brought to room temperature for 2 hours. The mixture is hydrolyzed with 2N HCl and stirred at room temperature for 1 hour. The ether layer is separated and the water layer is washed once more with ether. The combined ether layers is washed once with brine and dried with sodium sulfate. Evaporated to give 563 mg of the boronic acid as dark oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][N:14]([C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1
Reactant: COCC(=O)Cl
Reactant: O=C1Cc2cc(OCc3cccc(F)c3)ccc2C=CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1C=Cc2ccc(OCc3cccc(F)c3)cc2CC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
In a dried flask under an inert atmosphere, 50 mg (0.18 mmol) of 8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one were dissolved in 3 ml of dichloromethane, and the solution cooled to 0° C. Thereupon, 21 mg (0.21 mmol) triethylamine were added and stirring continued at 0° C. Finally, 18 μl (0.2 mmol) of methoxyacetic acid chloride were added. The reaction mixture was left to warm to RT and stirring continued for 18 h. For the working-up, the reaction mixture was evaporated under reduced pressure. For purification, the crude material obtained was directly transferred on a column and chromatographed on silica gel using a 99:1-mixture of dichloromethane and methanol as the eluent. There were obtained 15 mg (24% of theory) of 8-(3-fluoro-benzyloxy)-3-methoxyacetyl-1,3-dihydro-benzo[d]azepin-2-one as a white powder; MS: m/e=356 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:15])[CH3:14].Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:24]([C@H:23]([CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([N:17]1[C@@H:16]([CH:13]([CH3:15])[CH3:14])[CH2:20][O:19][C:18]1=[O:21])=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
22.50 ml (36.0 mmole) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 5.05 ml (36.0 mmole) of diisopropylamine in 100 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 7.84 g (30.0 mmole) of 4(S)-isopropyl-3-(3-phenyl-1-oxopropyl)-2-oxazolidinone (prepared as described in Preparation 12) in 50 ml of anhydrous tetrahydrofuran was added dropwise to the mixture. The mixture was then stirred for 1 hour, after which 14.26 ml (90.0 mmole) of benzyl bromoacetate were added to it. The mixture was stirred for 6 hours while the temperature of the reaction mixture was permitted to revert to room temperature. At the end of this time, the reaction mixture was mixed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was stripped from it by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 9.05 g (yield 74%) of the title compound as white crystals, melting at 118°-120° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[S:58][CH:59]=[C:60]([CH3:62])[CH:61]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[S:58][CH:59]=[C:60]([CH3:62])[CH:61]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1csc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(NC(=O)N2CCC(CCOc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanato-4-methylthiophene as the starting materials in 34% yield. LCMS for C30H33ClN7O2S (M+H)+: m/z=590.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH2:15][O:16][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2cccc(C(F)(F)F)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 4-[2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) in tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) followed by iodomethane (230 mg, 1.62 mmole). The mixture was stirred at 0° C. for three hours. The reaction was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate. Filtration, concentration gave a crude oil which was loaded onto a column of silica gel. Elution with 50% ethyl acetate/hexanes gave 4-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (190 mg, 92% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[NH2:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[OH:40][C:36]1[CH:35]=[C:34]([NH:33][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[O:31])[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Reactant: Nc1cccc(O)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)Nc5cccc(O)c5)c34)n(-c3ccccc3)c(=O)c12
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (25 mg, 0.06 mmol), 3-aminophenol (7 mg, 0.07 mmol) and diisopropylethylamine (41 μl, 0.23 mmol) were dissolved in DMF (1.5 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 140 μl, 0.24 mmol) was added dropwise and the reaction mixture stirred overnight at room temperature. The mixture was poured into ice and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 5% DCM/MeOH) to give 2 mg (6% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(Cl)(Cl)(Cl)Cl>C1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Reaction of 100 g of 5-chloro-2-nitrobenzoic acid and 103.3 g of phosphorus pentachloride in 400 ml of cyclohexane at reflux for 80 minutes followed by treatment of the crude product 3 times with carbon tetrachloride gave 5-chloro-2-nitrobenzoyl chloride. A solution of the acid chloride in 50 ml of tetrahydrofuran was added to a warm solution of 91.3 g of 5-aminotetrazole monohydrate in 500 ml of tetrahydrofuran and 20 ml of water. A precipitate formed, and the mixture was allowed to stand for 4 hours. It was then diluted with water and the solid was separated by filtration and air dried to give 5-chloro-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 268°-269° C., after recrystallization from dimethylformamide.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:21]([NH:22][C:23]3[C:24]4[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[S:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[CH2:36]([NH2:39])[CH2:37][CH3:38]>C(Cl)Cl>[CH2:36]([NH:39][C:33]([C:30]1[S:29][C:25]2[N:26]=[CH:27][N:28]=[C:23]([NH:22][C:21]3[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]4)=[N:17][CH:18]=[CH:19][CH:20]=3)[C:24]=2[C:31]=1[CH3:32])=[O:34])[CH2:37][CH3:38]
Reactant: CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCC(NC(=O)OC(C)(C)C)CC3)c12
Solvent: ClCCl
Product: CCCNC(=O)c1sc2ncnc(Nc3cccnc3OC3CCC(N)CC3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.1 g 4-[2-(4-tert-butoxycarbonylamino-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid, 39.689 μl chlor-trimethyl-propylenamine, 24 μl propylamine, 30.664 μl TEA and 5 ml DCM was stirred at rt overnight. The reaction mixture was washed successively with 0.1 M hydrochloric acid and 0.1 M sodium hydroxide solution, dried and filtered. The filtrate was concentrated. The residue was triturated with diethylether.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:34][CH3:35])[C:26]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]=O>CS(C)=O.COC(C)(C)C.[Cl-].[Na+].O>[CH3:35][O:34][C:25]1[CH:24]=[C:21](/[CH:22]=[C:14](/[C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH3:3])[CH:6]=3)[NH:10][CH:9]=2)\[C:15]#[N:16])[CH:20]=[C:19]([O:18][CH3:17])[C:26]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCOc1c(OC)cc(C=O)cc1OC
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Product: COCCOCOc1c(OC)cc(/C=C(\C#N)c2c[nH]c3ccc(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a suspension of NaH (60 mg, 80%, 2.5 mmol, 1.7 eq.) in DMSO (5 mL) was added, under an argon atmosphere, a solution of (5-methoxy-1H-indol-3-yl)-acetonitrile (331 mg, 1.8 mmol, 1.2 eq.) and 3,5-dimethoxy-4-(2-methoxy-ethoxymethoxy)-benzaldehyde (400 mg, 1.5 mmol, 1.0 eq.) in a mixture of DMSO (7 mL) and tert-butyl methyl ether (7 mL). The reaction apparatus was protected from light and the mixture was stirred at ambient temperature for 3 hours, and then treated with brine (10 mL). The mixture was extracted with ethyl acetate (3×30 mL), and the organic layer was washed with water and saturated aqueous ammonium chloride solution, and then dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: heptane/AcOEt, 70:30 to 50:50) to afford (Z)-3-[3,5-dimethoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-2-(5-methoxy-1H-indol-3-yl)-acrylonitrile as a yellow oil (100 mg) used in the next synthetic step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C=O)C>[OH:22][CH2:21][C:20]1[CH:24]=[CH:25][C:17]([C:16]([NH:12][NH:11][C:9](=[O:10])[C:8]2[CH:13]=[CH:14][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(=O)NN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(=O)NNC(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.5 %

Procedure:
4-Isobutylbenzohydrazide (2.10 g, 10.9 mmol) was added to a stirred solution of 4-hydroxymethylbenzoic acid (1.66 g, 11.2 mmol), HBTU (4.25 g, 11.2 mmol), diisopropylethylamine (1.45 g, 11.2 mmol) and DMF (50 mL) and stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (200 mL), washed with 5% NaHCO3 (aq.) and brine, dried (MgSO4), filtered and concentrated in vacuo to give a white solid. The solid was triturated with ethyl acetate and filtered to give the title compound (2.01 g, 56% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:9]([C:10](O)=[S:11])[C:8]=2[C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:9]3[C:10]([O:18][C:16](=[O:17])[C:8]=23)=[S:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c(C(O)=S)cccc1-c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=S)c2cccc(-c3ccccc3)c21
Temperature: 25 °C
Yield: 74.8 %

Procedure:
25.6 g (93.5 mmol) 3-phenylthio-phtalic acid and 26.4 mL (281 mmol) acetic anhydride were heated to reflux for 6 hours. The reaction mixture was allowed to cool down to room temperature. Upon standing over night, 3-phenylthio-phtalic anhydride precipitated from the medium. A first crop of 16.8 g of 3-phenylthio-phtalic anhydride was isolated by filtration and dried. The filtrate was evaporated to half of its volume and a second crop of 4.1 g of 3-phenylthio-phtalic anhydride was isolated. 20.9 g (87%) of 3-phenylthio-phtalic anhydride was isolated (m.p. 148-50° C.)
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]=[CH:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:20](Br)[CH:21]=[CH2:22].N>C1COCC1>[CH2:22]([CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH:9]=[CH:8][CH2:7][CH:3]12)[CH:21]=[CH2:20]
Reactant: O=C1CC2CC=CC2O1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1C(=O)OC2C=CCC21

Procedure:
Analogously to the procedures of Example 1, the title compound was prepared from 0.31 g (2.5 mmol) of 3,3a,4,6a-tetrahydro-cyclopenta[b]furan-2-one, 2.5 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.36 g (2.5 mmol) of allyl bromide in 7 ml of THF. Yield: 278 mg (67.8%) of a colourless oil. MS (DCI/NH3): m/e=182 [M+NH4+]
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[C:31]([NH:32][CH2:33][CH3:34])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:27]=[CH:28][C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][C:31]=1[NH:32][CH2:33][CH3:34]
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)cnc1Cl

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.101 mmol) and [2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-ethyl-amine (stage 153.1.1) to give the title compound as a yellow solid. (HPLC: tR 2.74 min (Method A); M+H=462 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.13-8.08 (m, 1H), 7.98-7.93 (m, 1H), 7.76-7.73 (m, 1H), 7.58-7.54 (m, 1H), 6.97-6.93 (m, 1H), 5.72 (t, 1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.26 (qt, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.22 (t, 3H))
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1Br)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>C1COCC1.C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
3-Benzyloxy-4-bromobenzoic acid, benzyl ester (33.00 g, 83.07 mmol) was placed in a three necked flask and the atmosphere was replaced, under vacuum, with argon using a Firestone valve. The solid was dissolved in THF (215 ml), with stirring, and then triethylamine (396 ml) was added. The mixture was cooled in an ice/water bath and the solution degassed five times as described above. Copper (I) iodide (127 mg, 0.66 mmol) and bis(triphenylphosphine)palladium (II) chloride (933 mg, 1.33 mmol) were quickly added and the solution degassed twice more. Trimethylsilylacetylene (17.6 ml, 124.6 mmol) was then added dropwise, by syringe, over ten minutes. The cooling bath was then removed and the solution allowed to slowly warm to ambient temperature. After 21 h TLC analysis (25% EtOAc/hexane) indicated that essentially all the starting material had been consumed. The solvents were removed by evaporation in vacuo and ethyl acetate (500 ml) and dilute brine (300 ml) were added. The organic fraction was separated and the aqueous phase was back extracted with ethyl acetate (1×250 ml and 1×100 ml). The total organic fraction was dried over sodium sulphate, filtered and evaporated to give a crude brown solid (36.2 g). The solid was dissolved in hot ethyl acetate (80 ml) where upon the title compound crystallised. This solid was removed by filtration, washed with ethyl acetate and dried in a vacuum oven at 40° C. to give pure title compound (13.75 g, yield 39%), mp=110.5-111.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](Cl)=[O:10])[O:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][NH:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C(N(CC)CC)C>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][NH:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])=[O:10])[O:4][N:3]=1
Reactant: O=C(NCC1CCCCN1)N1CCc2ccccc21
Reactant: Cc1noc(-c2ccccc2C(=O)Cl)n1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccccc2C(=O)N2CCCCC2CNC(=O)N2CCc3ccccc32)n1
Yield: 50 %

Procedure:
2-(3-Methyl-1,2,4-oxadiazol-5-yl)-benzoyl chloride (0.045 g, 0.2 mmol) in MDC (2.7 ml) was added to a solution of 2,3-dihydroindole-1-carboxylic acid (piperidin-2-ylmethyl) amide (0.05 g, 0.193 mmol) and triethylamine (0.1 ml, 0.72 mmol) in MDC (3 ml). After 20 h the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (8 ml). The organic layer was added directly onto a dry 10 g pre-packed silica gel cartridge and eluted with 10-100% ethyl acetate in hexane gradient to afford the title compound as a colourless solid (0.043 g, 50%). Mass Spectrum (API+): Found 446 (MH+). C25H27N5O3 requires 445.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:1]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:6][CH3:5])=[O:15])=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC(=O)Cl)cc1

Procedure:
A 20% solution of phosgene (170 mL, 0.33 mol) in toluene was added to a 500 mL pear-shaped flask (flame-dried, N2). To the flask was added methyl-p-hydroxybenzoate (42.6 g, 0.28 mol) with stirring. Through an addition funnel was added pyridine (26.7 mL, 0.33 mol) in toluene while the reaction mixture was cooled in an ice bath so that the temperature did not exceed 20° C. The solution turned a yellowish color during the addition. The reaction mixture was stirred for 3 h, at which point the mixture was filtered on a buchner funnel. The pyridinium salts were washed with toluene (150 mL) and the combined organic phase washed with 1 N HCl (2×), water (2×), dried over CaCI2 and Na2SO4, and the toluene removed in vacuo to yield yellowish crystals. After continued drying, the product (38 g, 63%) turned a greyish color. m.p. 52-53° C. (lit. 51-52° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[N:10]([O-])=[O:11].[Na+]>C(O)(=O)C>[OH:11][N:10]=[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: O=N[O-]
Reactant: N#CCc1cnccn1
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC(=NO)c1cnccn1
Yield: 88 %

Procedure:
Pyrazineacetonitrile (32 g), prepared as described in British Patent Specification No. 1 021 397, was dissolved in glacial acetic acid (250 ml). The solution was stirred and 1.2 equivalents of sodium nitrite (22.3 g) were added in small portions, while the temperature was kept under 20° C. After the addition, the reaction mixture was stirred at room temperature for another two hours. The title compound separated partly from the reaction mixture. On evaporation of the solvent under reduced pressure, a solid was obtained which on recrystallization from hot water yielded α-hydroxyiminopyrazineacetonitrile (35 g, 88%). Melting point >192° C. (dec.).