Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20]>>[CH3:14][O:15][C:16](=[O:22])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Product: CCC(=O)C(Cc1ccc(S(=O)(=O)CC)cc1)C(=O)OC

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-ethanesulfonylbenzene and 3-oxopentanoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:15]#[CH:16])=[CH:4][CH:3]=1.[CH2:22]([N:29]=[N+:30]=[N-:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH:16]=[C:15]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CC(NS(C)(=O)=O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(NS(C)(=O)=O)c1cn(Cc2ccccc2)nn1

Procedure:
Prepared according to the procedure described in Example 40, Step 2, using N-{1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-ynyl}-methanesulfonamide and benzyl azide.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1I.CN(C)C=O.C(N(CC)CC)C>[Cl-].[Na+].O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[C:3]#[C:2][CH2:1][OH:4]
Reactant: Clc1cc(Cl)c(I)c(Cl)c1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: OCC#Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 120 °C
Yield: 77 %

Procedure:
To a microwave vial were added propargyl alcohol (0.19 ml; 3.3 mmol), 1,3,5-trichloro-2-iodo-benzene (0.50 g; 1.6 mmol), N,N-dimethylformamide (6 ml), triethylamine (4 ml), bis(triphenylphosphine) palladium(II) chloride (0.11 g; 0.16 mmol) and copper iodide (31 mg; 0.16 mmol). The mixture was degassed under argon. The orange solution was heated in the microwave at 120° C. during 25 min. The mixture obtained was poured in brine and extracted three times with dichloromethane. Organic were combined, dried over sodium sulfate and evaporated under reduced pressure to provide the crude which was subject to flash chromatography (eluant: c-hexane/ethyl acetate 8:2). 290 mg (75% of theory) of 3-(2,4,6-trichloro-phenyl)-prop-2-yn-1-ol was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].C(C(CCCC)C=O)C>CCCCCCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2]
Reactant: CCCC=C(C=O)CC
Agent: CCCCC(C=O)CC
Solvent: CCCCCCC
Product: CCCCC(CC)CO

Procedure:
Heptane occurs as by-product in very limited amounts, from the hydrogenation via decarbonylation of 2-ethylhexenal and 2-ethylhexanal. The recovery of pure 2-ethylhexanol in the third stage occurs distillatively via the separation of a fraction of the first runnings by means of a first running column and separation of a distillation residue in a main product column. Although the separation of the components with boiling points below that of 2-ethylhexanol can take place at normal or slightly reduced pressure, industrially, due to the high boiling point of 2-ethylhexanol, the entire distillation is carried out at a reduced pressure of 50 to 200 torr. However, it is not possible under these conditions to separate 2-ethylhexanol completely from the higher boiling components in the main product column. The bottom product of the main product column must therefore be redistilled in a further column, the last runnings column, in order to separate the 2-ethylhexanol in the residue from the higher boiling components. A temperature below 180° C. is usually maintained in the bottom product with this distillation (last runnings distillation). At the head of the column, the remaining 2-ethylhexanol is obtained together with small amounts of the higher boiling substances as a last runnings fraction. This is recycled to the hydrogenation or distillation and is thereby subjected to a further distillation, so that finally, 2-ethylhexanol is almost completely separated from the higher boiling substances, which are removed at the bottom of the last runnings column. They consist of the reaction products of 2-ethylhexenal with itself or with n-butyraldehyde and constitute oxygen-containing compounds with more than 8 carbon atoms. The boiling points of the reaction products lie above that of 2-ethylhexanol.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:4]=1[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:6].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]([CH:11]([CH3:12])[CH3:13])[CH:8]([CH3:9])[CH3:10])=[O:6]
Reactant: COc1ccc(C(=O)N(C(C)C)C(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N(C(=O)c1ccc(O)cc1O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dimethoxy-N,N-bis(1-methylethyl)benzamide (3.0 g, 11.0 mmol) in 10 ml of dichloromethane at 0° C. is treated with 1N boron tribromide (33.0 mL, 33.0 mmol) and stirred at room temperature for 2 hours. The reaction is concentrated in vacuo, dissolved in 1N sodium hydroxide solution, and acidified with 1N hydrochloric acid to generate solid which is filtered to afford 2,4-dihydroxy-N,N-bis(1-methylethyl)benzamide as white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:30])[CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:19](=[O:31])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[N:32]([O-])=[O:33].[Na+]>C(O)(=O)C.O.CC(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:30])[C:23]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[N:32][OH:33])[C:19](=[O:31])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccncc3)[C@H]2SC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccncc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-(pyrid-4-ylacetamido)ceph-3-em-4-carboxylate (3.0 g.) in acetic acid (30 ml.) was stirred, cooled briefly in ice and treated dropwise over 3-4 minutes with a solution of sodium nitrite (1.38 g.), in water (10 ml.). The mixture was stirred at 20° for 30 minutes and was then diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation almost to dryness gave a residue which was dissolved in the minimum volume of acetone and added dropwise to stirred petroleum spirit (bp. 40°-60°). The resulting solid was collected, washed with petroleum spirit and dried to yield the title oxime as a white powder (2.9 g., 91%) which was shown (NMR) to be a syn-/anti-mixture (30:/0).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:4][O:3]1.[C:12]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2C(N[C:23](=[O:24])[C:18]=12)=O)(OCC)=[O:13].C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:12](=[O:13])[C:17]3[C:18](=[CH:19][CH:25]=[CH:26][CH:27]=3)[C:23]2=[O:24])[CH2:4][O:3]1
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: CC1(C)OCC(CCCN)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCCN2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propylamine (1.05 g, 6.60 mmol) and carboethoxyphthalimide (1.45 g, 6.60 mmol) in acetonitrile (10 mL) at room temperature was added triethylamine (0.92 mL, 6.60 mmol) in one portion and the resuting mixture was stirred at room temperature for 18 hours, evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with brine, 10% citric acid solution and brine, then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave an oil which was purified by column chromatography on silica using ethyl acetate-petroleum ether mixture as eluent to afford a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C:56]([CH3:59])([OH:58])[CH3:57]>CN(C)C=O.O>[OH:58][C:56]([CH3:59])([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CC(C)(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NCC(C)(C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min. A solution of 1-amino-2-methylpropan-2-ol (77 mg) in N,N-dimethylformamide (1 mL) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (150 mg, 65%) as colorless prisms. MS 533 (Me). mp 200-201° C.
Reaction SMILES: N.Cl[CH:3]([F:22])[C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)=[O:5].[NH2:23]C1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O.ClC(F)C(Cl)=O>CS(C)=O>[F:22][CH:3]1[N:23]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:4]1=[O:5]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(F)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Agent: O=C(Cl)C(F)Cl
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F
Reaction time: 16 h

Procedure:
NH3 is passed into a solution of 3.26 g. of 2-(α-chloro-α-fluoro-acetamido)-5-chloro-benzophenone, obtainable from 2-amino-5-chlorobenzophenone and α-chloro-α-fluoroacetyl chloride, in 15 ml. of DMSO at 50° for one hour. After stirring for 16 hours, the mixture is evaporated; 35 ml. of chloroform and 35 ml. of 13% NHO3 are added and the resulting salt is filtered off. The product is suspended in ethanol and neutralized with ammonia. Dilution with water gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH:7]1[CH3:19])#[N:2].[ClH:20]>C(OCC)C>[ClH:20].[CH3:19][CH:7]1[CH2:8][NH:9][CH2:10][CH2:11][N:6]1[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1CCCC#N
Agent: Cl
Solvent: CCOCC
Product: CC1CNCCN1CCCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
To a stirred solution of tert-butyl 4-(3-cyanopropyl)-3-methylpiperazine-1-carboxylate (1.3 g, 4.86 mmol) in diethyl ether (10 ml) was added hydrochloric acid (2 molar in ether, 10 ml, 20.00 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure and triturated with diethyl ether to yield the title compound 4-(2-methylpiperazin-1-yl)butanenitrile hydrochloride (1 g, 4.91 mmol, 24.54% yield)
Reaction SMILES: NN.[C:3]([O:7][C:8](=[O:28])[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([N+:25]([O-])=O)[CH:17]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>C1COCC1.C(O)C.[Ni]>[C:3]([O:7][C:8](=[O:28])[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([NH2:25])[CH:17]=2)[CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc([N+](=O)[O-])cc3ccoc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(N)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrazine (1.038 mL, 28 mmol) and raney-nickel (slurry in ethanol; 10 mL) were added to tert-butyl[1-(5-nitro-1-benzofuran-7-yl)piperidine-4-yl]carbamate (1.03 g, 2.85 mmol; Intermediate 48) in a mixture of THF (50 mL) and ethanol (150 mL). The mixture was stirred at room temperature for 16 h, filtered through a pad of Celite and concentrated in vacuo to afford 1.02 g (quantitative) of the title product. HPLC 95%, RT: 1.746 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 1.45 (s, 9H) 1.65-1.69 (m, 2H) 1.72-1.96 (m, 2H) 2.76-2.85 (m, 2H) 3.50-3.54 (m, 1H) 3.76 (d, J=12.62 Hz, 2H) 6.33 (d, J=1.98 Hz, 1H) 6.54 (d, J=1.98 Hz, 1H) 6.60 (d, J=2.23 Hz, 1H) 7.59 (d, J=1.98 Hz, 1H). LC-MS 332 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([NH:19][CH2:20][CH2:21][CH2:22]2)=[CH:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]=O>[Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C=C4NCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NCCC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a solution of 20-tert-butyldimethylsilyloxy-7β-methyl-4-azapregn-5-ene (23.9 g, 53.6 mmol, product of Step 8) in acetic acid (250 mL) was added platinum oxide (1.8 gm). The mixture was stirred overnight under hydrogen (1 atmosphere). The reaction mixture was filtered through a pad of Celite™ filter aid (trademark for diatomaceous earth) and the filtrate was coevaporated with toluene (3×500 mL) to remove all of the acetic acid. The residue was dissolved in chloroform and filtered again through a pad of Celite™ filter aid to remove residual catalyst. The solvent was removed by roto-evaporation to yield the title compound which was taken directly on to the next step without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[C:19]([C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:25])[N:11]3[CH2:26][CH2:27][NH:8][CH2:9][C@H:10]32)=[C:14]([C:21]([F:23])([F:24])[F:22])[CH:15]=1)#[CH:20]
Reactant: C#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (27 mg, 0.8 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 22 mg of a white solid. MS (ESI) 281 (M−Cl).
Reaction SMILES: Cl[Si:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl-].[NH4+].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][Si:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:16]
Reactant: CCCCCCCC[Si](C)(C)Cl
Reactant: CCO
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCC[Si](C)(C)OCC

Procedure:
An amount of 29.2 g of chlorodimethyloctylsilane, i.e. 0.14 mol, is gradually introduced over 2 h 30 into the reaction mixture. 75.4 g of absolute ethanol are added in order to prevent the mixture setting solid due to the formation of ammonium chloride crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:9](C3C4C(=CC(OCC5C=CC=CC=5)=C(OC)C=4)NC=3)=[CH:10][C:3]=12.CI>>[C:36]1([CH3:39])[CH:35]=[CH:34][C:33]([S:30]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][CH:2]=[C:3]3[CH:10]=[CH:9]2)(=[O:32])=[O:31])=[CH:38][CH:37]=1
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1OCc1ccccc1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1

Procedure:
4-Chloro-2-[1-methyl-5-methoxy-6-benzyloxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 89c, but using 2.5 g of 4-chloro-2-(5-methoxy-6-benzyloxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.335 ml of methyl iodide. After purification by flash chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents, argon), 2.1 g of 4-chloro-2-(1-methyl-5-methoxy-6-benzyloxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.CC1NC(=O)CC(=O)N=1.C(OCCO)C.[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:9][C:4]1[N:5]=[C:6]([Cl:8])[CH:7]=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: CC1=NC(=O)CC(=O)N1
Solvent: CCOCCO
Product: Cc1nc(Cl)cc(Nc2cccc(O)c2)n1
Temperature: 130 °C

Procedure:
4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) prepared based on the method described in Production Example 2A above using 2-methyl-1H-pyrimidine-4,6-dione instead of the 2-ethyl-1H-pyrimidine-4,6-dione, was slowly added to a 2-ethoxyethanol (5.0 mL) solution of 3-aminophenol (1.09 g, 10.0 mmol) and the reaction mixture heated for 4 hours at 130° C. The reaction was monitored by thin layer chromatography and, following the end of the reaction, the reaction mixture was cooled to room temperature and the precipitated white powder filtered off. The crude product filtered off was used in the subsequent reaction without further purification (1.76 g, crude yield 75%).
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:14])[C:9]([O:11]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)[O-].[Na+].S(=O)(=O)(O)O>C(O)(C)C>[N:1]1([CH2:7][CH:8]2[CH2:14][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:22][C:9]2=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C(CN1CCCCC1)C(=O)OCC
Reactant: NNc1ccccc1
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1NN(c2ccccc2)CC1CN1CCCCC1
Reaction time: 1 h

Procedure:
Ethyl 2-piperidinomethylacrylate (19.7g) was added in one portion to a boiling mixture of phenylhydrazine (10.8g) and sodium isopropoxide (2.3g sodium) in isopropanol (100 ml), giving rise to a vigorous foaming. The solution was boiled vigorously under reflux in order to avoid contact of the reaction mixture with air. After boiling for one hour, the solution was cooled rapidly and neutralised with sulphuric acid (50 ml, 2N). The mixture was extracted with chloroform (3 × 100 ml) and the chloroform solution was evaporated to dryness, giving a buff solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH2:19]Cl.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].[H-].[Na+]>CO>[CH3:26][O:25][C:23](=[O:24])[CH:22]([CH2:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])[C:21]([O:28][CH3:29])=[O:27]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2CCl)c(C)c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cc1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C)C(=O)OC

Procedure:
The title compound was prepared by reacting 4-chloro-3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine with dimethyl malonate/NaH in methanol. The title compound was isolated as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: COc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (154 mg, 1.63 mmol) was added in one charge to a stirred solution of 5-bromo-2-({[3-(methyloxy)phenyl]methyl}oxy)benzoic acid (may be prepared as described in Description 30; 275 mg, 0.82 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (188 mg, 0.98 mmol) and 1-Hydroxybenzotriazole (132 mg, 0.98 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 270 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of 4-bromomethyl-benzoic acid methyl ester 17h (1 g, 4.37 mmol), 3-trifluoromethylphenylboronic acid 15b (1 g, 5.25 mmol) and Pd(PPh3)4 (50 mg, 0.044 mmol) in dioxane (15 mL) was stirred at room temperature for 1 min. An aqueous solution of Na2CO3 (2M, 4 mL) was added. The resulting solution was heated at 90° C. for 5 h and was then cooled to room temperature. The reaction was partitioned between EtOAc and water. The organic phase was concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to give compound 17i.