Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li:2].[CH2:3]([C:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=[CH2:5]>CCOCC>[CH2:3]([C:6]1([Li:2])[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH:4]=[CH2:5]
Reactant: [Li]C
Reactant: C=CCC1=CC=CC1
Solvent: CCOCC
Product: [Li]C1(CC=C)C=CC=C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 0.105 mol of methyllithium in ether is added slowly to a solution, vigorously stirred at 0° C., of the β-propenylcyclopentadiene prepared in the preceding stage (a) in ether. The mixture is heated to ambient temperature (20° C.) and is kept stirred for 1 hours. A precipitate of β-propenylcyclopentadienyllithium is isolated by filtration, washed with ether 2′ 100 ml) and dried to give a white powder. 47.5 millimoles of zirconium tetrachloride dissolved in 100 ml of THF are added to a vigorously stirred solution of β-propenylcyclopentadienyllithium in 100 ml of THF at 0° C. The mixture is heated to ambient temperature (20° C.) and is stirred for 16 hours. The volatile compounds are removed under vacuum and the residue is extracted with ether (4′ 100 ml) and filtered. The product is obtained in the form of a white solid by slow cooling of the solution to −78° C. and recrystallization from cold ether.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.B(O)O>>[CH3:23][O:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:30]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: OBO
Product: COc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cn1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: [C:1]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:51])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:50])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:49])[N:34]([CH2:37][CH2:38][CH2:39][N:40](C(OC(C)(C)C)=O)[CH3:41])[O:35][CH3:36])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>O1CCOCC1.CO>[C:1]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:51])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:50])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:49])[N:34]([O:35][CH3:36])[CH2:37][CH2:38][CH2:39][NH:40][CH3:41])=[CH:31][CH:32]=2)[CH3:19])[CH2:12][CH2:11]1
Reactant: CON(CCCN(C)C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CNCCCN(OC)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
The compound (130 mg, 0.165 mmol) obtained in Example 87b was dissolved in a mixed solvent of 1,4-dioxane (1.6 mL) and methanol (1.6 mL), a 4 N hydrochloric acid-dioxane solution (0.412 mL, 1.65 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted (×3) with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography to give the title compound (48 mg; yield, 42%) as a colorless oily substance.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.O.[Cl-].[Na+].O>[C:16]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 89.8 %

Procedure:
To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol) in dioxane (5 mL), a solution of NaOH (0.50 g, 12.9 mmol) in water (5 mL) followed by a solution of benzoyl chloride (0.75 mL, 6.44 mmol) in dioxane (2 mL) under vigorous stirring were added. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with brine (20 mL), and extracted with ethyl acetate (2×25 mL). The organic extract was washed successively with brine (20 mL), saturated NaHCO3 (20 mL), saturated KH2PO4 (20 mL), and dried (Na2SO4). The solvents were evaporated to give the title compound (1.400 g, 90%) which was used in the next step of the synthesis without further purification. 1H NMR (CDCl3, HMDS), δ: 1.41 (s, 9H), 2.86 (t, J=5.0 Hz, 4H); 3.62 (t, J=5.0 Hz, 4H); 7.34 (s, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]([F:74])([F:73])[F:72])[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([NH:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]([F:74])([F:72])[F:73])[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63])=[O:7]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a solution of 3-bromo-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (100 mg, 0.36 mmol), PyBrOP (277 mg, 0.59 mmol) and diisopropylethyl amine (0.11 mL, 0.59 mmol) in DCM (6 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (161 mg, 0.36 mmol) [prepared according to Preparation 3]. After 16 h, the solution was concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (172 mg, 78%) as a white solid: LC-MS (ES) m/z=612 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:38])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21](CC3C=CC(OC)=CC=3OC)[S:20]2(=[O:37])=[O:36])=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[NH:21][S:20]2(=[O:36])=[O:37])=[CH:14][CH:13]=1)=[O:38]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)NCc1ccc(CN2CC(=O)NS2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
The title C compound, ({4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamic acid t-butyl ester (80 mg, 0.14 mmol) is stirred in equal volumes of CH2Cl2 and TFA (4 mL) for 16 h. The volatiles are evaporated and the residue is stirred in equal volumes of MeCN/water (5 mL) for 30 min. The mixture is filtered through a 0.2μ Acrodisc and the solvents are evaporated. The solid is washed with Et2O and dried to afford 2-amino-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide as a white solid: [M−1]−=311.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH:19](=O)[CH2:20][CH2:21][CH2:22][CH:23]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: O=CCCCC=O
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCCC3)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.403 mmol) obtained in Example 411 and 25%-glutaraldehyde (187 mg, 0.448 mmol) were dissolved in methanol (10 ml), and the resulting solution was stirred at room temperature for 40 minutes. Then, sodium cyanoborohydride (51 mg, 0.815 mmol) and acetic acid (0.2 ml) were added thereto, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with chloroform and separated by the addition of a 1N-aqueous sodium hydroxide solution, and the desired compound was further extracted from the aqueous layer with chloroform. The combined chloroform layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2, 100/4) to obtain 4-methyl-5-[(cis-3-piperidin-1-ylcyclohexyl)oxy]-1H-indazole (91 mg, yield 71.2%) as a white amorphous substance.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([OH:42])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Yield: 97 %

Procedure:
Dissolve tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (203 mg, 0.325 mmol) in 1,2-dichloroethane (3 ml) add TFA (3 ml, 38.9 mmol). The reaction was capped under a nitrogen atmosphere at 25° C. for 2 hrs. Reaction volatiles were removed in vacuo and the residue dissolved in 80 mL of ethyl acetate with heating. The solution was washed with 1N aqueous hydrochloric acid (2×40 mL), brine and dried over magnesium sulfate. The product solution was filtered, volatiles removed and the sample dried in vacuo at room temperature overnight to give 179 mg (97%) of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.74-1.03 (m, 4H) 1.06-1.31 (m, 6H) 1.32-1.50 (m, 3H) 1.56 (d, J=9.16 Hz, 2H) 1.77 (d, J=8.85 Hz, 2H) 1.86-2.18 (m, 5H) 2.83-2.91 (m, 1H) 3.60 (s, 3H) 3.64-3.89 (m, 4H) 3.88-3.93 (m, 4H) 3.95-4.08 (m, 1H) 4.43 (d, J=15.56 Hz, 1H) 5.64 (d, J=14.95 Hz, 1H) 6.99 (d, J=2.75 Hz, 1H) 7.07 (dd, J=8.70, 2.59 Hz, 1H) 7.48-7.56 (m, 2H) 7.85-7.94 (m, 2H) 8.15 (s, 1H). LC-MS retention time 1.65 min; 568 m/z (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([CH3:18])=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:24]N(C(OC)OC)C>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](/[CH:18]=[CH:24]/[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cncnc1
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(/C=C/N2CCCC2)cc1Oc1cncnc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2,5-dimethyl-4-nitrophenoxy)pyrimidine (0.7243 g, 2.95 mmol), pyrrolidine (0.345 mL, 4.13 mmol) and DMF-DMA (0.551 mL, 4.13 mmol) in DMF (3.0 mL) under nitrogen was heated at 115° C. After 45 min, the reaction was cooled to room temperature and concentrated in vacuo, followed by a short-path distillation. The crude residue was used in the subsequent step.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[O:24][CH3:25])[C:6]2[C:11](=[O:12])[NH:10][N:9]=[CH:8][C:7]=2[NH:13][C:14]=1[CH3:15])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:34]([O+](CC)CC)[CH3:35].CO>O>[C:1]([C:4]1[CH:5]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[O:24][CH3:25])[C:6]2[C:7]([NH:13][C:14]=1[CH3:15])=[CH:8][N:9]=[N:10][C:11]=2[O:12][CH2:34][CH3:35])(=[O:3])[CH3:2]
Reactant: COc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cn[nH]c(=O)c21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOc1nncc2c1C(c1ccc(C#N)cc1OC)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
65 mg (0.193 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydropyrido[2,3-d]pyridazin-4-yl)-3-methoxybenzonitrile are mixed under an argon atmosphere with 4 ml of abs. dichloromethane and 73.4 mg (0.386 mmol) of triethyloxonium tetrafluoroborate. After a reaction time of 2 hours at room temperature (reaction check by HPLC), conversion remains incomplete. Two further equivalents of triethyloxonium tetrafluoroborate are added. After a further reaction time of 3 h, the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 8 mg (11.3% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:12][CH3:13])[O:4][CH2:3]2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1cccc2c1CC(N)CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Temperature: 60 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
In a round bottomed flask, 2.2 mmol of 3-amino -5-methoxychroman (described in Patent EP 279,150) are dissolved in 6 ml of dimethylformamide in the presence of 2.4 mmol of N-(4-bromobutyl)phthalimide, 6.6 mmol of potassium carbonate and a catalytic amount of potassium iodide. The mixture is left stirring at 60° C. for 6 hours. After cooling, the solvent is evaporated off and, after aqueous hydrolysis, the crude reaction mixture is extracted with dichloromethane. After washing, drying and evaporation of-the organic phase, the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleum ether, 5:95).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH2:20]([N:24]1[C:28](=[CH2:29])[C:27]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:26][C:25]1=[O:35])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][C:27]3([O:26][C:25](=[O:35])[N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[C:28]3=[CH2:29])[CH2:30][CH2:31]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(=CCCBr)c2ccc(Cl)cc2)cc1
Reactant: C=C1N(CCCC)C(=O)OC12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C1N(CCCC)C(=O)OC12CCN(CCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)CC2
Reaction time: 5 h
Yield: 79 %

Procedure:
10.7 g of 4,4-bis(4-chlorophenyl)-3-butenyl bromide are added to the solution of 4.5 g of 3-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 45 ml of acetone containing 4.20 g of anhydrous potassium carbonate and 0.5 g of potassium iodide. The heterogeneous reaction mixture is refluxed under nitrogen while stirring for 5 hours. After evaporating the solvent under reduced pressure, water is added to the residue and extracted with benzene. The benzene phase is washed with water until halide-free, filtered through a silica gel bed and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title product in 79.0% yield, m.p.: 110°-111° C.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Br.BrCCBr.[Cl:17][Si:18]([CH3:24])([CH3:23])[Si:19](Cl)([CH3:21])[CH3:20]>C1COCC1.O>[Cl:17][Si:18]([CH3:24])([CH3:23])[Si:19]([CH3:21])([CH3:20])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]([CH3:2])=[CH:11]2
Reactant: CC1=Cc2cccc(Br)c2C1
Reactant: C[Si](C)(Cl)[Si](C)(C)Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: O
Product: CC1=Cc2cccc([Si](C)(C)[Si](C)(C)Cl)c2C1

Procedure:
To 7.97 g (0.332 mol) of magnesium turnings in 80 mL of THF a mixture of 33.4 g (0.160 mol) of 2-methyl-7-bromo-1H-indene, 30.0 g (0.160 mol) of 1,2-dibromoethane and 420 mL of THF was added dropwise with vigorous stirring at such rate that the mixture is refluxed. Further on, this mixture was additionally refluxed for 30 minutes. The obtained solution was added dropwise with vigorous stirring to a solution of 100 g (0.534 mol) of 1,2-dichloro-1,1,2,2-tetramethyldisilane in 100 mL of THF for 2 hours at room temperature (water bath cooling is required). The resulting mixture was stirred for 12 hours at ambient temperature and then evaporated to dryness. To the residue 100 mL of dry ether was added, and the obtained suspension was stirred for 20 minutes and then filtered through glass frit (G3). The precipitate was washed with 2×100 mL of ether. The combined filtrate was evaporated to dryness, the residue was dried and then rectificated in vacuum, b.p. 140° C.-145° C./1 mm Hg. Yield 26.3 g (58%) of the title product. 1H NMR (CD2Cl2): δ 7.22-7.32 (m, 3H, 4,5,6-H), 6.54 (m, 1H, 3-H), 3.39 (s, 2H, 1,1′-H), 2.21 (s, 3H, 2-Me), 0.66 (m, 3H, SiMe), 0.61 (m, 3H, SiMe), 0.59 (m, 3H, SiMe), 0.50 (m, 3H, SiMe). Anal. Calc. for C14H21ClSi2: C, 59.85; H, 7.53%. Found: C, 59.65; H, 7.72%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH3:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].N#N.F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C)C=O>[CH3:10][N:6]1[C:7]([CH3:9])=[CH:8][C:4]([NH:3][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)cc(C)n1C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])cc(C)n1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.0 g (0.2 mole) of commercially available 80% sodium hydride (in paraffin) are added to a solution of 18.2 g (0.1 mole) of ethyl 3-amino-1,5-dimethyl-1H-pyrrole-2-carboxylate in 200 ml of dry dimethylformamide at 0° C. under an inert gas atmosphere (N2). After 1 hour, the evolution of gas has subsided. 28 g (0.2 mole) of 2-fluoronitrobenzene are added dropwise in the course of 30 minutes. After 3 hours, the mixture is allowed to come to room temperature and is poured on to 100 g of ice and extracted several times with ethyl acetate. The combined extracts are washed with water and dried over sodium sulfate. The solvent is stripped off in vacuo. The resulting yellow-orange oil crystallizes completely after a short time. Yield: 22.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:10](/[C:28]([F:31])([F:30])[F:29])=[CH:11]\[C:12]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([CH3:27])[CH:15]=2)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:32][OH:33].[OH-].[Cs+]>C(Cl)(Cl)Cl.O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:10]2([C:28]([F:31])([F:30])[F:29])[O:33][N:32]=[C:12]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([CH3:27])[CH:15]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: NO
Agent: [Cs+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A 1500 mL reaction-vessel was charged at room temperature with 1-Anthracen-9-ylmethyl quininium chloride (2.93 g, 5.32 mmol) and tert-butyl 4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoate (12.7 g, 26.6 mmol) and dissolved in chloroform (700 mL). The mixture cooled down to −20° C. Then, a solution hydroxylamine (50 mass % in water, 3.3 mL) in water (16.7 mL) and cesium hydroxide (10.8 g, 71.8 mmol) in water (20 mL) were added simultaneously dropwise to the reaction mixture over 12 min. After the addition the reaction was kept 1.5 h at −20° C. after which time the conversion was complete. The reaction was brought to room temperature diluted with dichloromethane and washed three times with water. The organic phase was dried over MgSO4 and evaporated to yield 24.2 g of the crude title product. The product was purified over a silica gel column (eluent: EtOAc/Heptane) to obtain 12.6 gr of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#N.S(=O)(=O)(O)[OH:12].[CH2:16]([OH:18])[CH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:18][CH2:16][CH3:17])=[O:12]
Reactant: CCO
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccccc1Br
Product: CCOC(=O)Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 730.0 g of o-bromophenylacetonitrile in 2.9 l of absolute ethanol is added, dropwise, while stirring, 740 ml of concentrated sulphuric acid. The addition requires about two hours. The reaction mixture is heated under reflux for nine hours, poured into ice water, and extracted with 2.5 l of ether. The ether extracts are washed, dried, and concentrated. The residue is distilled to give 780.0 g of ethyl o-bromophenylacetate, bp. about 115°-117° (4mm), nD26 1,5434.