Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[N:6][CH:7]=1.O=[CH:27][C:28]([OH:30])=[O:29].FC(F)(F)C(O)=O>CN(C=O)C>[CH3:14][C:12]1[CH:13]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][CH2:27][C:28]([OH:30])=[O:29])[CH:7]=[N:6][CH:5]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(N)c2)c1
Reactant: O=CC(=O)O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(NCC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[3-(5-aminopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (20.0 mg, 0.058 mmol), oxoacetic acid (4.29 mg, 0.058 mmol) in DMF (0.579 mL, 0.1 M), and trifluoroacetic acid (8.92 μL, 0.116 mmol). was stirred for 1 hour at room temperature. Si-cyanoborohydride (123 mg, 0.116 mmol, 0.94 g/mmol) was added to the reaction mixture and stir for 12 hours at room temperature. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by reverse phase liquid chromatography (5:95 to 95:5, acetonitrile:water+0.1% v/v formic acid) afforded N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]glycine as the formic acid salt. MS APCI calc'd for C19H17F3N5O2 [M+H]+ 404. found 404. 1H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.96 (d, J=2.6 Hz, 1H), 7.89 (s, 1H), 7.53 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 2H), 3.91 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4]I.C([Li])CCC.[CH3:19][Sn:20](Cl)([CH3:22])[CH3:21].O>O1CCCC1>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4][Sn:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C=CI)c1ccc(Cl)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C=C[Sn](C)(C)C)c1ccc(Cl)cc1
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A stirring solution of 4.8 grams (0.016 mole) of 3-methyl-3-(4-chlorophenyl)-1-iodo-1-butene in 50 mL of tetrahydrofuran is cooled to about -90° C., and 6.9 mL (0.01 8 mole) of n-butyllithium (2.5M in hexane) is added dropwise at a rate to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of the addition, the reaction mixture is stirred at -90° C. for 30 minutes. After this time, a solution of 3.7 grams (0.019 mole) of trimethyltin chloride in 10 mL of tetrahydrofuran is added dropwise at a rate sufficient to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of addition, the reaction mixture is again stirred at -90° C. for 30 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then poured into 150 mL of water and extracted with 150 mL of diethyl ether. The ether extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4.8 grams of 3-methyl-3-(4-chlorophenyl)-1-trimethylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1ccc(C)c(C)c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C)c(C)c1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 40 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 0.94 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(3,4-dimethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 40, above] and 31.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.26 g of the title compound as white crystals, melting at between 137° and 139° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC2C=CC(OC)=CC=2)=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)C2CCC(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (12 g, 24.1 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred for 3 hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The residue was stirred 1 hour with about 100 ml ethanol and the white solid was filtered (byproduct). The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with toluene/acetone. Yield: 6.8 g=74%. The product can be activated and esterified directly to a drug or further modified as described below.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][C:42]=1[Cl:43])[O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH:36][C:37](=[O:39])[CH3:38])=[N:35][C:30]2=[CH:29][CH:28]=1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:37]([NH:36][C:34]1[S:33][C:31]2[C:30]([N:35]=1)=[CH:29][CH:28]=[C:27]([O:26][C:25]1[CH:40]=[CH:41][C:42]([Cl:43])=[C:23]([NH:22][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:24]=1)[N:32]=2)(=[O:39])[CH3:38]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(N)c3)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (120 mg, 0.537 mmol) produced in Example C61(v) was dissolved in tetrahydrofuran (3.0 mL) and N,N-dimethylformamide (0.01 mL), oxalyl chloride (56.87 μL, 0.672 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, toluene (10 mL) was added to the residue, and the mixture was again concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (3.0 mL), N-[5-(3-amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (90 mg, 0.269 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (80 mL), the organic layer was washed with aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), further purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0→ethyl acetate/methanol=90/10), and crystallized from diethyl ether to give the title compound (81 mg, 56%) as white crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH3:19].[OH-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([NH2:17])[CH2:19][CH2:18]2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C2(N)CC2)nc1
Reaction time: 0.5 h

Procedure:
5-(tert-Butyldimethylsilanyloxymethyl)-pyridine-2-carbonitrile was dissolved in tetrahydrofuran (10 ml), titanium tetraisopropoxide (0.62 ml) was added thereto, and a solution of ethylmagnesium bromide in tetrahydrofuran (1 mol/l, 4.83 ml) was added dropwise. The mixture was stirred for 1 hr 30 min. To the reaction mixture was added 1N aqueous sodium hydroxide solution (6 ml) and tetrahydrofuran (20 ml) was further added, and the mixture was stirred and filtered. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (192 mg).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[N:21]3[C:16]([O:17][CH2:18][CH2:19][CH2:20]3)=[C:15]([C:22]([NH:24][C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH3:27])=[O:23])[CH:14]=2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(C1NC(Br)=C(C(OCC)=O)C=1)=O)C.C1([C@@H](N)CC)C=CC=CC=1>>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[N:21]3[C:16]([O:17][CH2:18][CH2:19][CH2:20]3)=[C:15]([C:22]([NH:24][C@H:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH3:27])=[O:23])[CH:14]=2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)n2c1OCCC2)c1ccccc1
Agent: CCOC(=O)c1cc(C(=O)OCC)c(Br)[nH]1
Agent: CC[C@H](N)c1ccccc1
Product: CC[C@H](NC(=O)c1cc(C(=O)N[C@@H](CC)c2ccccc2)n2c1OCCC2)c1ccccc1

Procedure:
6.0 mg of 3,4-dihydro-2H-pyrrolo[2,1-b][1,3]oxazine-6,8-dicarboxylic acid bis-[((S)-1-phenyl-propyl)-amide] were prepared in analogy to the preparation of 3,4-dihydro-2H-pyrrolo[2,1-b][1,3]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide], starting from 5-bromo-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (354 mg, 1.22 mmol; prepared according to the procedure described in US 2004/0209886), and (S)-1-phenyl-propylamine (284 mg, 2.10 mmol). LC/MS (method 4): Rt=1.31 min; m/z=446.24 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.CC([O-])(C)C.[K+].Br[C:15]1[CH:16]=[C:17]2[N:26]([CH3:27])[CH:25]=[CH:24][C:18]2=[N:19][C:20]=1[C@@H:21]([NH2:23])[CH3:22]>COCCOC>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([C:15]2[CH:16]=[C:17]3[N:26]([CH3:27])[CH:25]=[CH:24][C:18]3=[N:19][C:20]=2[C@@H:21]([NH2:23])[CH3:22])[CH2:5]1
Reactant: COC1CNC1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: COC1CN(c2cc3c(ccn3C)nc2[C@H](C)N)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a microwave vial containing 3-methoxyazetidine hydrochloride (500 mg, 4.05 mmol) were added KOt-Bu (1339 mg, 11.93 mmol) and DME (8 mL) under an atmosphere of nitrogen. The mixture was heated to 90° C. in a sand bath. A solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (461 mg, 1.82 mmol) in DME (8 mL) was added dropwise to the hot suspension. The mixture was stirred at 90° C. overnight. Additional KOt-Bu (1956 mg, 17.43 mmol) was added and the mixture was heated to 90° C. for 90 minutes. The reaction mixture was subsequently concentrated in vacuo. The residue was dispersed in DMSO/MeOH (1:1, 10 mL), filtered, and purified by preparative HPLC eluting with 15-40% ACN in water (with 0.035% NH4HCO3). The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (469 mg, 99%). ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.
Reaction SMILES: [C:1]([C:7]#[N:8])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].S(=O)(=O)(O)[OH:10].C(=O)([O-])[O-].[Na+].[Na+]>O.[Cl-].[NH4+]>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:7]([NH2:8])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)C(=O)C#N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)C(=O)C(N)=O
Reaction time: 12 h
Yield: 51.2 %

Procedure:
55.5 g (0.5 mole) of pivaloyl cyanide and 2 g of ammonium chloride were introduced into a 500 ml three-necked flask. The mixture was cooled to -5° to 0° C. and 100 ml of concentrated sulphuric acid was added dropwise at this temperature. 18 ml (1 mole) of water were then added dropwise, also at -5° to 0° C. The reaction mixture was subsequently stirred at -5° to 0° C. for 12 hours and was then poured onto a solution of 350 g of sodium carbonate in 600 ml of water. It was extracted twice with 300 ml of methylene chloride each time. The combined organic phases were washed with 300 ml of water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. Recrystallization from petroleum ether gave 66 g (51.2% of theory) of trimethylpyruvic acid amide of melting point 67° to 69° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N-:14]1.[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[O:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 91.5 %

Procedure:
4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) and potassium 1,3-dioxoisoindolin-2-ide (2.0 g, 10.9 mmol) were placed in microwave vial (0.5-2 ml) and NMP (12.0 ml) was added. The reaction mixture was heated at 200° C. using microwave (Biotage, Initiator) for 1 min. After cooling to rt, the reaction mixture was added dropwise to stirring water which resulted in formation of precipitate. The solid was collected, washed with water and dried under stream of nitrogen to afford the title compound (2.89 g, yield: 92%). 1H-NMR (400 MHz, CDCl3) δ 7.26 (s, 2H) 7.43 (d, 2H) 7.81-7.87 (m, 3H) 7.91 (dd, 2H) 7.95-8.05 (m, 3H) 8.33 (d, 1H)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:35][CH:36]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 50 °C
Yield: 83.1 %

Procedure:
A solution of 6-[4-(2-methoxycarbonylphenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.141 g) in MeOH/H2O (5/1 mL) containing NaOH (0.087 g) was heated at 50° C. for 2 h. The reaction mixture was cooled in ice and acidified with 0.5 N HCl. It was extracted with EtOAc and the extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: CHCl3/MeOH: 100/1 to 50/1, Chromatotron) afforded the titled compound (114 mg). MS (m/z) 531 (M++Na).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Product: CCOC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 39 %

Procedure:
In analogy to the procedure described for the preparation of example 3, (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) was reacted with ethyl chloroformate to give the title compound as a off-white powder in 39% yield. MS: 322.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:5]=1[N:6]([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9])[CH3:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:27]=[O:28]>>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH:27]=[O:28])[C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:5]=1[N:6]([CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCN(CCC)c1cc(OCC)ccc1OCC
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)c1cc(OCC)c(C=O)cc1OCC
Temperature: 0 °C

Procedure:
2,5-Diethoxy-4-formyl-N,N-di-n-propylaniline was prepared in situ by taking 2,5-diethoxy-N,N-di-n-propylaniline (2.65 g., 0.01 mole) in a mixture of N,N-dimethylformamide (10 ml.) and phosphorus oxychloride (1.68 g., 0.011 mole) and heating on a steam bath for two hours. The mixture was then poured into ice water to give the coupling solution.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][Si](C(C)(C)C)(C)C)=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].C(#N)CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.N#N.[C:65]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])(=[O:68])[CH:66]=[CH2:67].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:70]([O:69][C:65](=[O:68])[CH:66]=[CH:67][C:2]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CN2C(=O)c3ccccc3C2=O)c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 95 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A 12 L flask was charged with 2-[2-bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzyl]-isoindole-1,3-dione (461 g, 1.03 mol), propionitrile (7 L), tri-ortho-tolyl phosphine (76.0 g, 0.250 mol) and diisopropyl ethyl amine (365 mL, 2.10 mol). The reaction mixture was degassed/purged with N2 (3×), and tert-butyl acrylate (465 mL, 3.17 mol) was added. After degassing/purging one time, palladium (II) acetate (28.0 g, 0.125 mol) was added. The stirred mixture was degassed/purged with N2 three times and heated to 95° C. for 20 h. The mixture was filtered through a hyflo cake, washed with acetonitrile, and concentrated to a brown oil (841 g). The residue was dissolved in THF (3.5 L), and tetrabutylammonium fluoride (TBAF, 650 mL, 0.65 mol, 1M in THF) was added. After 1 h, additional TBAF (95 mL) was added. The mixture was rotated on the rotary evaporator for 10 min and was concentrated to crude product (987 g). This material was purified by silica gel chromatography (toluene/ethyl acetate, 100/0 to 75/25) to give the title compound (340 g, 86.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10]>C1C=CC=CC=1>[Cl:14][C:13]([Cl:16])([Cl:15])[CH2:12][O:11][C:9]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Product: CN1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1

Procedure:
N-methylpiperazine (2 g) is dissolved in 20 ml benzene and reacted with a solution of 4.5 g 2,2,2-trichloroethyl chloroformate in 20 ml benzene, with stirring and cooling in an ice bath. After stirring for 2 hours the resulting crystals are collected by vacuum filtration, washed with ether and dried under water-pump vacuum at room temperature, to give the hydrochloride of the title compound, m.p. 238°-240° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][O:35][CH3:36]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Product: COCCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 2-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Stage 30.1.1, 39 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.71 min (Method A); M+H=474 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.15-8.02 (m, 2H), 7.97-7.89 (m, 1H), 7.59-7.51 (m, 1H), 7.11-7.02 (m, 2H), 7.00-6.94 (m, 1H), 4.16-4.07 (m, 2H), 3.94-3.84 (m, 6H), 3.70-3.64 (m, 2H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].CC(C)([O-])C.[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 12.4 g (0.053 mol) of 2-hydroxy-5-bromo-phenylacetic acid in 125 ml of dimethylformamide is combined with 14 g (0.125 mol) of potassium tert.butoxide. After 15 minutes at ambient temperature 18.5 g (0.108 mol) of benzylbromide are added. The reaction solution is stirred for 3 hours at ambient temperature, poured onto ice water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is dissolved in 100 ml of ethanol and after the addition of 50 ml of 2N sodium hydroxide solution stirred for 3 hours at ambient temperature. The solvent is distilled off, the residue is adjusted to pH 4 with 2N hydrochloric acid. After extraction with ethyl acetate the organic phases are dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (8:2).
Reaction SMILES: [S:1]1[C:5]([CH2:6]O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:13][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1
Reactant: OCc1cc2ccccc2s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of commercially available benzo[b]thiophen-2-ylmethanol (123 mg; 0.73 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (242 mg; 0.73 mmol), and with PPh3 (191 mg; 0.73 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)benzo[b]thiophene as a yellow/orange oil which was directly used for the next reaction.