Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:14]=2)[O:9][CH2:8]1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:34][N:35]([CH3:40])[CH2:36][C:37]([O:17][C@H:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:14]=2)[O:9][CH2:8][C@H:7]1[O:6][C:5]1[CH:30]=[CH:31][CH:32]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:38]
Reactant: COc1cccc(O[C@@H]2COc3ccc(OCc4ccc5ccccc5n4)cc3[C@@H]2O)c1
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2COc3ccc(OCc4ccc5ccccc5n4)cc3[C@@H]2OC(=O)CN(C)C)c1
Reaction time: 18 h

Procedure:
To a solution of the title product of Example 26 (0.493 g), 4-(dimethylamino)pyridine (0.226 g) and N,N-dimethylglycine hydrochloride (0.193 g) in 30 ml of CH2Cl2 was added a solution of dicyclohexylcarbodiimide in 5 ml of CH2Cl2. After stirring 18 hours, by-product dicyclohexyl urea was recovered by filtration and the filtrate stripped to an oily solid which was chromatographed on a silica gel column with ether as eluant to yield purified title product, 0.44 g. 1H-NMR(CDCl3)delta(ppm): 2.15 (s, 6H), 3.15 (s, 2H), 3.80 (s, 3H), 4.30 (d, J=5Hz, 2H), 4.90 (m, 1H), 6.30 (d, J=3, 1H), 6.30-8.30 (m, 13H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[NH2:26]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CCOC(=O)c1ccc(Cn2ccc3ncnc(Cl)c32)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c32)o1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of ethyl 5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (300 mg) in 1-methyl-2-pyrrolidone (2.0 mL) was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (360 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (30 mL) and extracted with a mixed solvent (45 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (440 mg) as pale-yellow powder crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][CH2:15][N:16]3[C:21](=[O:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])[CH:8]=[N:7]1.Br[CH2:39]C1C=C(NC(=O)OC(C)(C)C)C=CC=1.BrC(C1C=C(NC(=O)OC(C)(C)C)C=CC=1)C>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]([N:6]2[CH:10]=[C:9]([C:11]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:12]=3[CH2:13][CH2:14][CH2:15][N:16]4[C:21](=[O:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=3[CH3:33])[CH:8]=[N:7]2)[CH3:39])[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(N)c5)c4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Agent: CC(Br)c1cccc(NC(=O)OC(C)(C)C)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(C(C)c5cccc(N)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-(bromomethyl)phenylcarbamate was replaced with tert-butyl 3-(1-bromoethyl)phenylcarbamate. LCMS, [M+H]+=509.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([Mg]Cl)(C)C.[CH:15]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:31]2([OH:32])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:28]([CH:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:29]2=[O:30])=[C:4]([OH:9])[CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of 3,4-difluorophenol (10.33 g, 79.4 mmol) in anhydrous tetrahydrofuran (60 mL) at 0° C. under nitrogen was added isopropyl magnesium chloride (39.7 mL, 79.4 mmol), and the solution was stirred at ambient temperature for 3 h. Tetrahydrofuran was removed by rotary evaporation, and the residue was redissolved in anhydrous dichloromethane (140 mL). The solution was cooled to 0° C. under nitrogen, then N-benzhydryl isatin (13.77 g, 43.9 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 3 days, the reaction was quenched with aqueous saturated ammonium chloride (60 mL) and concentrated in vacuo. The residue was re-dissolved in ethyl acetate (150 mL) and washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was precipitated from diethyl ether to yield 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (12.08 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.23 (br s, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H), 6.90 (s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz, 1H), 6.56-6.51 (m, 1H), 4.13 (br s, 1H); MS (ES+) m/z 426.2 (M−17).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:25][N:26]=[C:27]=[O:28]>C(N(CC)CC)C>[CH3:25][NH:26][C:27]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: Nc1ccc(Oc2ccc3sncc3c2)cc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(Oc2ccc3sncc3c2)cc1
Yield: 85 %

Procedure:
24.2 parts of 5-(4'-aminophenoxy)-benzisothiazole, 400 parts of toluene, 1 part of triethylamine and 11.4 parts of methyl isocyanate were heated at 80° C. for 12 hours, and the reaction mixture was then evaporated down under reduced pressure. 25 parts (85% of theory) of 5-(4'-methylaminocarbonylaminophenoxy)-benzisothiazole of melting point 178° C. were obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH:27]1([CH2:26][C@H:20]([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:21](=[O:22])[N:23]([CH3:24])[CH3:25])[CH2:29][CH2:28]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CN(C)C(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (S)-2-amino-3-cyclopropyl-N,N-dimethyl-propionamide hydrochloride (1:1) (Example 25b) as starting materials, and isolated (80 mg, 86%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 373.2231 (M+H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30].C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(=O)N(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), dimethylcarbamoyl chloride (72.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent is was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow powder (42.8 mg).
Reaction SMILES: CC(C[C@H](C[NH2:11])CC(O)=O)C.C([CH:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18](O)=[O:19])C(C)C.C(OC(=O)C)(=O)C.[NH4+].[OH-]>>[C:18]([NH2:11])(=[O:19])[CH2:17][CH2:16][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Reactant: CC(C)C[C@H](CN)CC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: NC(=O)CCCC(=O)O

Procedure:
Several processes were reported for the synthesis of (S)-Pregabalin. One such process is illustrated in drugs of the future, 24 (8), 862-870 (1999), represented as scheme-1. In which 3-isobutylglutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenyl ethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the (R)-enantiomer, compound 6. Finally, a Hoffmann's degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that, it requires separating the two enantiomer thereby resulting in the loss of half of the product, such that the process cost is high.
Reaction SMILES: NC1N([C@@H]2CC[C@H](C(OC)=O)CC2)C2C=C(CO[Si](C(C)C)(C(C)C)C(C)C)C=CC=2N=1.C([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][C@H:41]([N:44]2[C:48]3[CH:49]=[C:50]([CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)[CH:51]=[CH:52][C:47]=3[NH:46]/[C:45]/2=[N:60]\[C:61](=[O:69])[C:62]2[CH:67]=[CH:66][C:65](F)=[CH:64][CH:63]=2)[CH2:40][CH2:39]1)=[O:37])C>>[C:36]([C@@H:38]1[CH2:43][CH2:42][C@H:41]([N:44]2[C:48]3[CH:49]=[C:50]([CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)[CH:51]=[CH:52][C:47]=3[N:46]=[C:45]2[NH:60][C:61](=[O:69])[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH2:40][CH2:39]1)(=[O:37])[NH2:35]
Reactant: CCNC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Agent: COC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Product: NC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CN4CCCCC4)cc32)CC1

Procedure:
The title compound was prepared in 5 steps from cis-methyl 4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate using a method analogous to the preparation of (E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide. MS m/z=460.2 [M+H]. Calc'd for C27H33N5O2: 459.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.45 (m, 2H) 1.46-1.58 (m, 4H) 1.60-1.82 (m, 4H) 2.08-2.25 (m, 2H) 2.29-2.45 (m, 4H) 2.54-2.61 (m, 1H) 2.61-2.87 (m, 2H) 3.40-3.56 (m, 2H) 4.56-5.01 (m, 1H) 6.87-6.94 (m, 1H) 7.12-7.22 (m, 1H) 7.31-7.41 (m, 1H) 7.43-7.53 (m, 4H) 7.54-7.63 (m, 1H) 7.96-8.52 (m, 2H) 12.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:24])[F:25])=[CH:20][CH:19]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: OCCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.79 g (10.5 mmol) of methyl 5-fluorosalicylate, 20 g (10.5 mmol) of 2-(4-trifluoromethyl-phenyl)ethanol and 2.76 g (10.5 mmol) of triphenylphosphine are introduced into 50 ml of THF and, at 0° C., a solution of 1.83 g (10.5 mmol) of DEAD in 10 ml of THF is added dropwise. The mixture is stirred at RT overnight and the volatile components are then removed in vacuo. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.09 g (58% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C([Li])CCC.C1(O[C:34]#[N:35])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:34]#[N:35])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(C#CC#N)cc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 2.60 g of 4-(2,2-dibromovinyl)-4'-pentylbiphenyl in 50 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 14.5 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was warmed to -10° C. within 10 minutes and then, after renewed cooling to -78° C., treated with a solution of 1.5 ml of phenyl cyanate in 10 ml of absolute tetrahydrofuran. The mixture was subsequently stirred at -78° C. for a further 30 minutes, then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.51 g) on silica gel with hexane followed by 2% ethyl acetate/petroleum ether and subsequent recrystallization from methanol gave 1.02 g (58%) of (4'-pentyl-4-biphenylyl)propiolonitrile as colourless crystals (purity 99.6%); m.p. (C-N) 51.0° C., cl.p. (N-I) 120.2° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=2)[C:10]([Br:24])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1cc(Br)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution under N2 of 6-(4-fluorophenyl)indole-1-carboxylic acid t-butyl ester (2.00 g, 6.42 mmol), prepared as in step 1, in THF (36 mL) was added N-bromosuccinimide (1.26 g, 7.08 mmol) in a single portion and the clear-orange solution was stirred overnight at ambient temperature. The reaction mixture was diluted with ether (500 mL) and extracted with aqueous NaHSO3 (1-2M, 250 mL) and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a viscous, clear-yellow oil (2.58 g), which solidified on standing.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[C:29]3[CH2:31][NH:32][CH2:33][CH2:34][C:28]3=[N:27][C:26]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:21][CH2:20]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:17]=1[O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:30]=[C:29]3[CH2:31][N:32]([C:1](=[O:3])[CH3:2])[CH2:33][CH2:34][C:28]3=[N:27][C:26]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(C(C)=O)C4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (9 μL, 0.095 mmol) was added to a solution of 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (25.2 mg, 0.048 mmol) and pyridine (11.5 μL, 0.143 mmol) in DCM (500 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (25.2 mg, 93%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.6 Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.15 (m, 2H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.93 (m, 1.1H), 3.04-3.14 (m, 2H), 3.42-3.50 (m, 2H), 3.75 (s, 3H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.09-4.19 (m, 1H), 4.35-4.42 (m, 1H), 4.55 (br s, 2H), 6.67 (dt, J=9.0, 1.4 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 458.4.
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[C:3]([O:9][CH3:10])[O:4][Si](C)(C)C.ClCCl.Br[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.CO>CCCCCCC.O.[Cl-].[Zn+2].[Cl-]>[CH3:10][O:9][C:3](=[O:4])[C:2]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)([Cl:11])[Cl:1]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: COC(O[Si](C)(C)C)=C(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)C(Cl)(Cl)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 liter flask equipped with an argon inlet was charged with crude (2,2-dichloro-1-methoxy-vinyloxy)-trimethylsilane (129.1 g, approximately 0.389 mol) and anhydrous dichloromethane (100 ml). To the resulting solution was added 1-bromoadamantane (75.2 g, 0.349 mol) and anhydrous zinc chloride (6.56 g, 48 mmol). The resulting mixture was allowed to stir at room temperature overnight. The resulting red-brown mixture was diluted with heptane (600 ml) and water (300 ml). The organic layer was separated and washed with water (2×100 ml), 1 N sodium bicarbonate (3×150 ml), and water (2×200 ml). The resulting solution was filtered though a pad of Celite 545 and filtrate was concentrated at reduced pressure to give a colorless solid. This material was dissolved in boiling methanol (250 ml). The resulting solution was allowed to cool to room temperature for 1 hour. After cooling to approximately 5° C. for 2 hours, the solid was collected by filtration and washed with cold methanol:water (94:6; 4×50 ml) to give adamantan-1-yl-dichloro-acetic acid methyl ester (Formula VII) as a colorless solid: 75.0 grams (77.3% based on 1-bromoadamantane); mp 76.3° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:14].CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][N:5]2[CH:6]=[CH:2][CH:3]=[C:4]2[C:7]([O:9][CH3:10])=[O:8])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Br)c[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (1 g, 4.9 mmol) and 2-bromo-1-(4-methoxyphenyl)ethanone (1.23 g, 5.3 mmol) in DMF (30 mL) was added potassium tert-butoxide (0.60 g, 5.4 mmol) portionwise at −15° C. The mixture was stirred at that temperate for 15 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous HCl (1M) and then extracted with EtOAc (3×100 mL). The organic layers were washed with brine, water and then concentrated in vacuo to give a liquid. This was azeotroped with toluene to give a residue corresponding to methyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate. ESI-MI m/z [M+H]+ 353.8. The crude was used in the next step without purification
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:10][C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C)c1O
Reactant: BrCCCCBr
Product: COc1cccc(C)c1OCCCCBr

Procedure:
Analogously to Example 50b, 2.50 g of 2-methoxy-6-methylphenol and 2.67 ml of 1,4-dibromobutane are used to prepare the title compound. Rf=0.58 (1:1 EtOAc-heptane); Rt=5.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[N:6][CH:7]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ncc(Br)cc1[N+](=O)[O-]

Procedure:
Prepared according to procedure G using 5-bromo-2-chloro-3-nitropyridine (25 g, 105 mmol) and potassium carbonate (44 g, 316 mmol), dimethyl malonate (18 mL, 158 mmol) in DMF (105 mL, 105 mmol). After purification dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate was obtained as a dark liquid. Mass Spectrum (ESI) m/e=333 [(M+1) (79Br)] and 335 [(M+1) (81Br)].