Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: COC(C(=O)O)c1c(F)cccc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1F

Procedure:
(RS)-(2,6-Difluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-phenyl)-2-methoxy-acetamide. Off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)[CH:30]=[O:31].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1CCCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:30]=[O:31])=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(C=O)nc3N21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.885 g (4R,9aR)-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 60 mL toluene at −78° C. was added 8.72 mL of a ca. 1.3 M solution of sec. butyl lithium in cyclohexane over 10 min. The orange mixture was stirred at −78° C. for 30 min. To the resulting viscous solution was added 1.00 mL dimethylformamide and the mixture was stirred at −78° C. for 1.5 h. To the reaction mixture was added 100 mL of a 10% citric acid solution in water. The phases were separated and the organic phase was evaporated to dryness and purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.585 g (4R,9aR)7-fluoro-6-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as yellow-orange crystals; m.p.: 139–140° C. and 0.800 g (4R,9aR)-7-Fluoro-8-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.O>CN(C=O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(F)cc1
Reactant: Nc1ccc(S)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(NC(=O)c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a solution of Example 238b (2.5 g, 8.5 mmol) in DMF (50 mL) was added CsCO3 (5.5 g, 17.0 mmol), and 4-aminothiophenol (1.0 g, 8.5 mmol). The mixture was heated at 80° C. for 16 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (60:30:10) to give the desired product (1.5 g, 46%).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17]Br)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C([Mg]Br)C.[Mg].BrCC.[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:29][Mg]Cl>C1COCC1>[CH3:14][C:6]1[C:7]([OH:13])=[C:8]([CH3:12])[C:9]2[CH2:10][CH2:11][C@:2]([CH2:16][CH2:17][CH2:41][C@@H:39]([CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:34][CH2:33][CH2:32][CH:28]([CH3:29])[CH3:27])[CH3:42])[CH3:40])([CH3:1])[O:3][C:4]=2[C:5]=1[CH3:15]
Reactant: CC(C)CCCC(C)CCCC(C)C[Mg]Cl
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 86 %

Procedure:
3.13 g (10 millimoles) of (2RS)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were dissolved in 10 ml of absolute THF. A solution of ethyl-magnesium bromide which had been prepared by reacting 0.25 g (10.3 millimoles) of magnesium in 3 ml of THF with a solution of 1.1 g (10.0 millimoles) of bromoethane in 5 ml of THF and stirring for 1 hour at +40° C. was added dropwise to the above solution at -20° C. The resulting reaction mixture was stirred for 1 hour at -20° C. and then there were added to it the (2RS,6RS)-2,6,10-trimethyl-1-undecyl-magnesium chloride solution prepared in Example 2a, followed by 0.7 ml of an 0.5-molar solution of di-lithium tetrachlorocuprate in absolute THF. The batch was then stirred for 3 hours at -20° C. and 16 hours at room temperature. The reaction mixture was worked up as described in Example 1c and 3.7 g of α-tocopherol were isolated by bulb tube distillation at 220° C./0.2 mbar. This corresponds to a yield of 86% of theory.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>C(O)C>[C:20]([O:19][C:15]([CH2:16][CH2:17][NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCO
Product: CCO[Si](CCCNCCC(=O)OC(C)(C)C)(OCC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
In dehydrated ethanol, 22.1 g (100 mmol) of 3-aminopropyltriethoxysilane was dissolved, and to the solution, was added 12.8 g (100 mmol) of t-butyl acrylate, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 32.5 g of the objective compound was obtained by removing solvent.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH3:25])=[N:15][N:16]2[CH3:24])=[O:11])([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[N+](=[CH2:28])=[N-]>CN(C)C=O>[C:1]([C:4]([NH:9][C:10]([C:12]1[C:20]([C:21]([O:23][CH3:28])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([CH3:25])=[N:15][N:16]2[CH3:24])=[O:11])([CH3:8])[CH:5]([CH3:6])[CH3:7])(=[O:3])[NH2:2]
Reactant: C=[N+]=[N-]
Reactant: Cc1nn(C)c2ccc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)c12
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c(C)nn2C)c1C(=O)NC(C)(C(N)=O)C(C)C

Procedure:
A solution of 4-[(1-Carbamoyl-1,2-dimethylpropyl)carbamoyl]1,3-dimethyl-1H-indazole-5-carboxylic acid (0.720 g, 2.07 mmol) in dry dimethylformamide is treated with sufficient ethereal diazomethane to give a permanent yellow color. The excess diazomethane is quenched with acetic acid, and the reaction mixture is concentrated in vacuo. The resultant residue is chased 2 times with xylene recrystallized from 50% aqueous methanol to give the title product as a white solid, mp 221°-222° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.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>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
A 250-mL 3-necked round-bottom flask was charged with a solution of 4-bromo-3-nitrobenzaldehyde (11.5 g, 50.00 mmol, 1.00 equiv) in toluene (80 mL). To this was added phenylboronic acid (6.7 g, 54.92 mmol, 1.10 equiv), followed by the addition of a solution of K2CO3 (13.8 g, 100.00 mmol, 2.00 equiv) in water (50 mL). To the mixture was added Pd(PPh3)4 (1.2 g, 1.04 mmol, 0.02 equiv) in one portion. The resulting solution was stirred at 110° C. for 15 hours. Upon completion, the reaction mixture was cooled down to room temperature. The resulting solution was diluted with 1000 mL of Et2O. The solids were filtered out. The resulting organic layers were washed with water (3×300 mL), dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:50) to afford 2-nitrobiphenyl-4-carbaldehyde as yellow solid (6.7 g, 59%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 79 %

Procedure:
To a nitrogen de-gassed solution of methyl 2-(2-ethynylphenyl)acetate (I4) (0.137 g, 0.788 mmol) in dry DMF (7 mL) were added triethylamine (0.366 mL, 2.63 mmol) followed by tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I24) (0.300 g, 0.657 mmol), triphenylphosphine (0.026 g, 0.098 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.046 g, 0.066 mmol) and CuI (0.019 g, 0.098 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I25) (0.310 g, 79% yield) as a yellow sticky oil; 1H NMR (400 MHz, d6-DMSO) δ 10.44 (s, 1H), 8.81 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (td, J=7.6, 1.3 Hz, 1H), 7.50-7.34 (m, 2H), 7.24 (d, J=8.6 Hz, 2H), 4.02-3.87 (m, 4H), 3.61 (s, 3H), 2.90-2.51 (m, 4H), 1.88 (d, J=12.0 Hz, 1H), 1.76-1.55 (m, 2H), 1.51-1.34 (m, 10H). LCMS Method C: rt 6.98 min; m/z 539.2 [M−C4H9(t-Bu)+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:23](=[O:24])[N:5]2[CH2:6][CH2:7][N:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)(=[O:12])=[O:11])[CH2:9][CH:4]2[CH2:3]1.[H-].[Na+].Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>CN(C)C=O>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:14]=[C:13]([S:10]([N:8]2[CH2:7][CH2:6][N:5]3[C:23](=[O:24])[CH:2]([O:1][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=4)[CH2:3][CH:4]3[CH2:9]2)(=[O:12])=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C(O)CC2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CCN12
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(Oc2ccc(C(F)(F)F)cn2)CC2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CCN12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product from Example 217B (23 mg, 0.063 mmol) in anhydrous N,N-dimethylformamide (0.6 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 2.78 mg, 0.069 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, and 2-bromo-5-(trifluoromethyl)pyridine (21 mg, 0.095 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was partitioned between water and ethyl acetate (3×), and the combined organic layers were concentrated in vacuo and purified on C18 silica gel using a solvent gradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid). The title compound was obtained as a colorless solid (22 mg, 68%). 1H NMR (300 MHz, CDCl3) δ ppm 1.58-1.68 (m, 0.5H) 2.03-2.49 (m, 3H) 2.88-3.21 (m, 1.5H) 3.72-4.08 (m, 3H) 4.21 (dd, J=13.39, 3.22 Hz, 1H) 5.50-5.74 (m, 1H) 6.88 (t, J=8.82 Hz, 1H) 7.69-7.85 (m, 2H) 7.88-8.00 (m, 2H) 8.02 (s, 1H) 8.26-8.43 (m, 1H); MS (ESI) m/z 510 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[C:34]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH:33]=[N:32][C:31]=23)[CH:22]=1)=[O:19])(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[C:34]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[CH:33]=[N:32][C:31]=23)[CH:22]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Yield: 49.6 %

Procedure:
TFA (2 ml) was added slowly to a stirred suspension of [2-(3-{3-[6-(4-Fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]phenyl}ureido)-ethyl]carbamic acid tert-butyl ester (390 mg, 0.80 mmol) in CH2Cl2 (4 ml) at RT. After 1 hour the volatiles were removed in vacuo. The residue was taken up in MeOH and loaded on a SCX cartridge (20 g). Eluting with 2M NH3. MeOH and removal of the solvent in vacuo gave the title compound (155 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[N+:20]([O-])=O)[C:15]#[N:16])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:23])[NH:6]2.C(O)(=O)C.O.[NH4+].[OH-]>[Fe].C(O)C>[NH2:20][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[NH:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][C:5](=[O:23])[NH:6]2)=[C:2]([Cl:1])[N:10]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-ylamino)-4-nitrobenzonitrile (0.41 g, 1.23 mmol) was added glacial acetic acid (30 mL), water (75 mL) and ethanol (150 mL), followed by iron powder (Aldrich, 0.69 g, 12.3 mmol, 10 equiv.) and the reaction mixture was stirred at 90° C. for 15 min (LC-MS monitoring), when it became a clear dark orange solution. It was cooled to r.t., then concentrated NH4OH (50 mL) was added to bring the pH to 11. The reaction mixture was stirred at r.t. for 30 min. Repeated extractions into ethyl acetate, then into 25% isopropanol in CH2Cl2 (total volume 2 L), drying of the combined organic extracts, and in vacuo evaporation of the solvent provided the desired product as a brown solid, which was used in the next step without further purification. MS (EI) m/z 302.1 (MH)+.
Reaction SMILES: CC12C(C)(C)C(C([O:13][CH2:14][C@@:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[O:17])=O)(CC1)OC2=O.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].Cl>ClCCl.C(OCC)(=O)C>[CH3:41][S:42]([O:13][CH2:14][C@@:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)=[O:17])(=[O:44])=[O:43]
Reactant: CC12CCC(C(=O)OC[C@](C)(O)C(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)(OC1=O)C2(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@](O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
439 mg of chiral diol (5C) of Example 22 was dissolved in 20 ml of dichloromethane. The solution was cooled to 0° C. (ice). 170 mg of triethylamine was added. 174 mg of methanesulfonyl chloride was dissolved in 5 ml of dichloromethane and slowly added to the diol solution. After the addition was completed, the mixture was allowed to warm to room temperature. After 25 minutes at room temperature, the reaction mixture was analyzed with HPLC; there was still 27% of diol present. Next 70 mg of methanesulfonyl chloride was added. After 10 minutes at room temperature, the reaction was completed. 60 ml of ethyl acetate and 60 ml of 0.5 N aqueous HCl were added. The organic layer was washed subsequently with 60 ml of water and 60 ml of saturated NaHCO3, dried (Na2SO4), filtrated and evaporated to dryness. Purification of the residue by column chromatography (Merck silica gel 60; eluens: ethyl acetate) afforded the title compound as a green/black oil. Isolated yield: 473 mg. 1H-NMR confirmed the expected structure (2S-enantiomer). HPLC: 94% purity.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cccnc1
Product: N#Cc1cc(-c2cccnc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (50 mg, 69%), MS (ISN) m/z=289.4 [(M+H)+], mp 272.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:28](=[O:29])[NH2:27])[CH:35]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc(C(N)=O)c2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-aminocarbonylphenyl-boronic acid in analogy to Example 2b): MS (ISN): 497.2 and 499.2 (M−H)−.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH:26]2[CH2:28][CH2:27]2)[C:10]1=[O:29])C1C=CC=CC=1>CO.[H][H].[Pd]>[CH:26]1([N:11]2[C:12]3[N:19]=[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[C:17]([F:25])=[CH:16][C:13]=3[C:14](=[O:15])[N:9]([OH:8])[C:10]2=[O:29])[CH2:28][CH2:27]1
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(C2CC2)c(=O)n1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(C2CC2)c(=O)n1O
Yield: 85.9 %

Procedure:
A suspension of 3-benzyloxy-1-cyclopropyl-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example K-2, 60 mg, 0.152 mmol) and 10% Pd/C (30 mg) in MeOH (3 mL) was stirred at room temperature in hydrogen atmosphere provided by a balloon for 30 minutes. Filtration and concentration of the filtrate gave a solid residue, which was further washed with 10% of dichloromethane/hexane to give 40 mg of the title compound as powder, mp 238° C. (decomp.).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:33][C:34]1[N:39]=[CH:38][C:37](Br)=[CH:36][N:35]=1>O1CCCC1.O.O.[Pd](Cl)Cl>[CH3:33][C:34]1[N:39]=[CH:38][C:37]([CH:1]=[CH2:2])=[CH:36][N:35]=1
Reactant: C=C[B-](F)(F)F
Reactant: Cc1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cnc(C)nc1
Temperature: 25 °C

Procedure:
A solution of potassium vinyltrifluoroborate (666 mg, 4.97 mmol; Aldrich), palladium(II) chloride (18 mg, 0.099 mmol; Aldrich), triphenylphosphine (78 mg, 0.298 mmol; Aldrich), cesium carbonate (4.86 g, 14.91 mmol; Aldrich), and 2-methyl-5-bromopyrimidine (867 mg, 4.97 mmol; AniChem) in tetrahydrofuran/H2O (9:1; 10 mL) was heated at 85° C. under a nitrogen atmosphere for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, concentrated, and the crude material was purified by flash chromatography (silica gel, 5-60% ethyl acetate in hexanes) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 2.73 (s, 3H), 5.44 (d, J=11.10 Hz, 1H), 5.86 (d, J=17.85 Hz, 1H), 6.63 (dd, J=17.85, 11.10 Hz, 1H), 8.66 (s, 2H); MS (DCI/NH3) m/z 121 (M+H)+, 138 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([NH-])(C)C.[Li+].Br[CH2:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21].Cl>O1CCCC1.O.C1CCCCC1>[CH2:20]([CH:19]([CH2:22][CH3:23])[CH2:18][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:21]
Reactant: CCC(CC)CBr
Reactant: O=C(O)C1CCCCC1
Agent: CC(C)[NH-]
Agent: Cl
Agent: [H-]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A suspension of 60% sodium hydride (980 mg) in tetrahydrofuran (80 ml) was stirred at room temperature, and a tetrahydrofuran solution (10 ml) containing cyclohexanecarboxylic acid (3.00 g) was added dropwise thereto. After completion of addition, a mixture was stirred for 1 hour and cooled to 0° C., followed by adding a cyclohexane solution (18.7 ml) containing 1.5 M lithium isopropylamide dropwise thereto. Then, after stirring at room temperature for 1.5 hours and cooling to 0° C., a tetrahydrofuran solution (10 ml) containing 1-bromo-2-ethylbutane (4.64 g) was added dropwise thereto. The solution was gradually warmed to room temperature and stirred overnight. Water and a 10% hydrochloride solution were added to this reaction solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After drying, the resulting solution was concentrated to obtain 1-(2-ethylbutyl)cyclohexanecarboxylic acid (3.17 g, yield: 64%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[Br:1]
Reactant: O=C(O)CCCOc1ccccc1Br
Reactant: CO
Product: COC(=O)CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.4 g of 4-(2-bromophenoxy)-butyric acid in 22 ml of methanol is mixed with 1 g of Amberlyst 15 and stirred for 5 hours at room temperature. Then, it is filtered from the Amberlyst 15, the filtrate concentrated by evaporation, the residue is taken up in diethyl ether, washed with dilute sodium carbonate solution, dried (Na2SO4) and concentrated by evaporation. 1.5 g of 4-(2-bromophenoxy)-butyric acid methyl ester is obtained as a colorless oil.