Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:27](F)=[CH:26][CH:25]=[CH:24][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](F)[C:16]=2[C:22]#[N:23])[C:7]=1[C:8]#[N:9])#[N:2].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:43][C:44]1[CH:45]=[C:46]([OH:50])[CH:47]=[CH:48][CH:49]=1>>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:17]2[C:16]([C:22]#[N:23])=[C:15]([CH:20]=[CH:19][CH:18]=2)[O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:6]([O:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:27]([O:50][C:46]4[CH:47]=[CH:48][CH:49]=[C:44]([NH2:43])[CH:45]=4)[C:3]=3[C:1]#[N:2])[C:7]=2[C:8]#[N:9])=[CH:32][CH:31]=1
Reactant: N#Cc1c(F)cccc1Oc1cccc(Oc2cccc(F)c2C#N)c1C#N
Reactant: Nc1ccc(O)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1c(Oc2ccc(N)cc2)cccc1Oc1cccc(Oc2cccc(Oc3cccc(N)c3)c2C#N)c1C#N
Temperature: 25 °C
Yield: 48.5 %

Procedure:
Into a 250 mL round bottom flask equipped with stir bar, condenser and nitrogen inlet was charged 2,6-bis(2-cyano-3-fluorophenoxy)benzonitrile (8.00 g, 21.4 mmol), 4-aminophenol (2.34 g, 21.4 mmol), potassium carbonate (3.56 g, 25.8 mmol) and N-methyl-1-pyrrolidone (NMP, 140 mL). The mixture was stirred at 100° C. for 24 hours until GC/MS showed no remaining reactant. It was allowed to cool to room temperature, followed by the addition of 3-aminophenol (2.34 g, 21.4 mmol) and potassium carbonate (3.56 g, 25.8 mmol). The mixture was stirred at 100° C. for 24 hours until GC/MS showed no remaining reactant. It was filtered and then the filtrate was poured into about 500 mL of saturated NaCl aqueous solution, followed by extraction with ethyl acetate (3×500 mL). The organic layer was combined and washed with distilled water (3×500 mL). It was then dried over sodium sulfate and filtered. Carbon black was added to the solution, which was then stirred at 65° C. for 30 minutes. It was passed through a Celite filter to remove carbon, and the solvent was removed by a rotary evaporator. A small amount of NMP residue in the product was removed by refluxing it in ethanol (75 mL). Product was collected by filtration and dried overnight at 80° C. in a vacuum oven to afford 5.73 g (48.5%) of a beige solid, m.p. 196.2-197.8° C. 1H-NMR (DMSO-d6): 5.16 (s, 2H, Ar—H), 5.37 (s, 2H, Ar—H), 6.29-6.31 (dd, 1H, Ar—H), 6.34-6.35 (t, 1H, Ar—H), 6.46-6.47 (dd, 1H, Ar—H), 6.60-6.65 (m, 3H, Ar—H), 6.78-6.80 (d, 1H, Ar—H), 6.88-6.93 (t, 3H, Ar—H), 6.96-6.98 (d, 1H, Ar—H), 7.07-7.15 (m, 3H, Ar—H), 7.58-7.62 (t, 1H, Ar—H), 7.64-7.68 (t, 1H, Ar—H), 7.78-7.80 (t, 1H, Ar—H). Elemental analysis: Calcd: C, 71.86; H, 3.84; N, 12.70. Found: C, 71.50; H, 3.87; N, 12.64.
Reaction SMILES: CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:36]([OH:38])=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[C:39]1([CH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:56])[C@@H:50]([CH2:52][CH2:53][S:54][CH3:55])[NH2:51])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1.C(OCC)(=O)C>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:36]([NH:51][C@@H:50]([C:49]([NH:48][CH2:47][CH2:46][CH2:45][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:56])[CH2:52][CH2:53][S:54][CH3:55])=[O:38])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: CSCC[C@@H](N)C(=O)NCCCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
N-methylmorpholine (485 mg.), then a solution of pivalyl chloride (579 mg.) in tetrahydrofuran (5 ml.), were added to a solution of N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine in tetrahydrofuran (35 ml.) maintained at -20° C., and the mixture was stirred at that temperature for about 10 minutes. A solution of N-(3-phenylpropyl)-D-methioninamide (1.50 g.) and N-methylmorpholine (485 mg.) in tetrahydrofuran (60 ml.) was then added, and stirring was continued at -20° C. for two hours and then at room temperature overnight. Ethyl acetate (150 ml.) was added. The mixture was washed three times with saturated aqueous sodium bicarbonate, three times with aqueous citric acid (5%), twice with water and twice with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum. Crystallization of the residue from ethyl acetate-hexane afforded as a white solid [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N-(3-phenylpropyl)-D-methioninamide (680 mg.; m.r. 158°-159° C.; [α]D25 +55.4°, c=1 methanol).
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].C(S(N1CCC2(C(=O)N(C3C=CC(C(O)C(F)(F)F)=CC=3)CC2)CC1)(=O)=O)C(C)C.[F:49][C:50]([F:62])([F:61])[C:51]([C:54]1[CH:59]=[CH:58][C:57](I)=[CH:56][CH:55]=1)([OH:53])[CH3:52]>>[CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[N:14]([C:57]3[CH:58]=[CH:59][C:54]([C:51]([OH:53])([CH3:52])[C:50]([F:61])([F:62])[F:49])=[CH:55][CH:56]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(O)(c1ccc(I)cc1)C(F)(F)F
Reactant: CC(C)CS(=O)(=O)N1CCC2(CCNC2=O)CC1
Agent: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(O)C(F)(F)F)cc3)C2=O)CC1
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(C)(O)C(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared in analogy to example 162 step B) from 8-(isobutylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one, product of example 167 A) and 1,1,1-trifluoro-2-(4-iodo-phenyl)-propan-2-ol (synthesis: H. Urata et al, Tetrahedron Letters; 1991; p 91). White crystalline solid. MS (ESI): 463.2 (MH+).
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].C1(C)C=CC(S(C[N+:17]#[C-])(=O)=O)=CC=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].O>O1CCCC1>[NH:17]1[CH:2]=[CH:5][C:21]([C:20]([O:24][CH3:25])=[O:23])=[CH:22]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a suspension of potassium tert-butoxide (17.9 g) in tetrahydrofuran (200 mL) was added dropwise a solution of p-toluenesulfonylmethyl isocyanide (25.2 g) and methyl acrylate (11.8 mL) in tetrahydrofuran (200 mL) over 30 min. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a white solid (yield 6.56 g, 41%).
Reaction SMILES: CO.[O:3]=[CH:4][CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1.[BH4-].[Na+]>C(O)(=O)C>[OH:3][CH2:4][CH:5]=[C:6]1[CH2:7][CH2:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:11]1
Reactant: COC(=O)C1CCC(=CC=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCC(=CCO)CC1
Temperature: 3 °C
Yield: 68.7 %

Procedure:
A solution was prepared from 77 ml of methanol and 13.0 g of methyl 4-(oxoethylidene)cyclohexanecarboxylate and cooled to 3° C. with an ice-water bath. With vigorous stirring, 3.1 g of sodium borohydride was added in portions over 30 minutes. The reaction was allowed to stir for an additional hour at 3° C. before glacial acetic acid (1 ml) was added to quench the reaction and the methanol was removed under reduced pressure. The residue was taken up in 200 ml of dichloromethane and partitioned with 400 ml of water. The organic layer was separated and washed with 200 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting oil was purified on the Prep LC (30% ethyl acetate/hexane, 250 ml/min., 2 min./cm, 2 columns, Rt =13 min.) to give 11.5 g of fairly pure product. Bulb-to-bulb distillation on the Kugelrohr at 150°-160° C./0.8 mm yielded 9.03 g (69%) of methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate. 1H NMR (CDCl3 60 MHz) δ 5.40 (t, 1 H); 4.10 (d, 2 H); 3.70 (s, 3 H); 2.9-1.3 (10 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.ClCC(=O)C[C:23]([O:25][CH3:26])=O.FC1C=CC(N=C=O)=CC=1.COCCO>O1CCOCC1.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH2:17][CH2:23][O:25][CH3:26])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Reactant: COC(=O)CC(=O)CCl
Agent: O=C=Nc1ccc(F)cc1
Agent: [Zn]
Solvent: COCCO
Solvent: C1COCCO1
Product: COCCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.063 g, 0.25 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, 2-methoxyethanol (0.2 mL, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0048 g, 0.0050 mmol) in anhydrous dioxane (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 120° C. for 1 h. Cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel(chloroform/ethyl acetate) to afford 2-methoxyethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.024 g, y. 33%).
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]C1C=CC(C(=O)C)=CC=1.C(OC)(=O)CC>>[F:14][C:4]1[CH:5]=[CH:6][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:2][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCC(=O)OC
Product: CCC(=O)CC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 0.525 g of 4′-fluoroacetophenone and 0.73 mL of methyl propionate to yield 120 mg of Intermediate 32: TLC analysis: Rf=0.77 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.98 (d, 2H, J=8.3), 7.7 (d, 2H, J=8.3), 6.12 (s, 1H), 1.55 (s, 3H); low resolution mass spectrum (ES+) 195 (MH+)
Reaction SMILES: [C:1](NCCCl)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:12][CH2:13][N:14](CC)CC.C(Cl)Cl>CN(C=O)C>[C:1]([CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN

Procedure:
Compounds of formula IX may be prepared according to Scheme V. Alkylation of the secondary amine in a compound of formula VII or formula VIIa with 2-(N-Boc amino)ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988, 36, 3125) in the presence of Et3N in a solvent such as CH2Cl2 or DMF gives the N-Boc ethylamine derivative of formula XI. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2Cl2 to give naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane of formula IX.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:3]=1[NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[CH2:9][CH2:8]1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>O1CCCC1>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][C:3]2[N:4]([CH2:5][CH2:6][N:7]3[CH2:12][CH2:11][N:10]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:14]=4)[CH2:9][CH2:8]3)[C:31](=[O:32])[NH:1][C:2]=2[CH:28]=1
Reactant: COc1ccc(NCCN2CCN(c3ccc(OC)c(C(F)(F)F)c3)CC2)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[nH]c(=O)n2CCN1CCN(c2ccc(OC)c(C(F)(F)F)c2)CC1
Reaction time: 24 h

Procedure:
2-Amino-4-methoxy-N-{2-[4-(4-methoxy-3-trifluoromethyl-phenyl)piperazin-1-yl]-ethyl}-aniline (2.5 g, 6 mmol) is dissolved in 30 ml tetrahydrofurane; 1.5 g (9 mmol) carbonyldiimidazole is added portionwise to the resulting solution. The mixture is left at room temperature under stirring for 24 h. After evaporation to dryness, the residue is purified by silicagel chromatography (methylene chloride/methanol/32% aqueous ammonia 95:5:0.5). The crude title compound is triturated with ethylether.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:27]([O:26][C:24]([N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
4-{[tert-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid methyl ester was suspended in ethanol (30 mL) and sodium hydroxide (4 N, 8.1 mL) was added. The reaction mixture was stirred overnight. The mixture was concentrated to dryness, suspended in water (100 mL), acidified with hydrochloric acid (8.5 mL, 4 N) and extracted with ethyl acetate (100 mL). The aqueous phase was extracted once more with ethyl acetate (30 mL) and the combined organic phases were washed with water (3×50 mL), dried with magnesium sulphate and concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and n-heptane to afford 1.75 g of 4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}-benzoic acid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[C:20]3[CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:10]1([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[C:20]3[CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC[C@@H]1Cc1cn(C(=O)c2ccccc2)c2ccc(OC3CCCCC3)cc12
Reaction time: 15 h
Yield: 20.1 %

Procedure:
Benzoyl chloride (0.10 mL, 0.86 mmol) was added to a solution of (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3g, ~75 mg, 0.24 mmol), triethylamine (0.20 mL, 1.4 mmol) and DMAP (23 mg, 0.19 mmol) in dichloromethane (2.5 mL). The mixture was stirred for 15 h. prior to quenching with water (25 mL) and extraction into dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. Purification by flash chromatography (silica gel, 2M methanolic ammonia in chloroform (1.5-3.3%) yielded (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-benzoylindole (20.1 mg, 20%, HRMS-FAB+ for C27H32N2O2 : calculated MH+ :417.25421; found MH+ :417.25475).
Reaction SMILES: [F-:1].[K+].C(O)COCCO.C1(C)C=CC=CC=1.Br[CH:18]([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:23])[CH2:19][CH2:20]Cl>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:18]2([F:1])[CH2:20][CH2:19]2)=[O:23])=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: [F-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)C1(F)CC1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
2000 g (34.5 mol) of potassium fluoride are introduced into 7 liters of diethylene glycol, and the mixture is treated with 500 ml of toluene at room temperature. The toluene is distilled off at 150° C., and the mixture is then allowed to cool to 100° C., and 1500 g (5 mol) of 4-chloro-phenyl 1-bromo-3-chloro-n-propyl ketone are added in portions in the course of 15 minutes. The reaction mixture is heated for 4 hours at 150° C. and then cooled and poured into 10 liters of water. The resulting mixture is extracted five times with 2 liters of toluene per extraction, and the combined organic phases are washed with water, dried over magnesium sulphate and concentrated by stripping off the solvent under reduced pressure. The residue which remains is distilled under a high vacuum, and the distillate collected is subjected to fractional distillation under a high vacuum, using a spinning band column. In this manner, 100 g (10% of theory) of 1-fluoro-cyclopropyl 4-chlorophenyl ketone are obtained in the form of a liquid of boiling point 70°-76° C. at 0.03 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:43][CH3:44])=[C:4]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:30][CH2:29]2)=[O:17])[CH:5]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].[OH-].[Na+]>ClCCl.CO>[CH3:52][S:53]([NH:1][C:2]1[C:3]([O:43][CH3:44])=[C:4]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:32][CH2:33]2)=[O:17])[CH:5]=[C:6]([C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[CH:7]=1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cc(C(F)(F)C(F)(F)F)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@@H]5CCCN5C)CC4)c3n2C)cc(C(F)(F)C(F)(F)F)cc1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
70 mg (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(3-amino-2-methoxy-5-pentafluoroethyl-phenyl)-amide are dissolved in 2 ml dichloromethane, combined with 36 μl triethylamine, and 20 μl methanesulphonic acid chloride are added dropwise to this mixture. It is stirred for 2 hours, a further 20 μl methanesulphonic acid chloride and 36 μl triethylamine are added and then it is stirred for 1.5 hours. Then 2 ml of methanol and 600 μl of 2 N sodium hydroxide solution are added. The mixture is stirred for 2 hours, the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/(methanol/ammonia in methanol (saturated) 9:1) 99:1 to 85:15).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OCc4ccccc4)cccc3C2C1
Temperature: 80 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.10 mmol) from Example 72, Step B, in N,N-dimethylformamide (1.5 mL) was added benzyl bromide (0.017 L, 0.15 mmol) and potassium carbonate (41 mg, 0.29 mmol). The resulting mixture was warmed to 80° C. After 4 h the reaction was cooled to room temperature, diluted with ethyl acetate, washed with 50% saturated aqueous sodium chloride, and the the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (31 mg, 80%). MS (ESI) 395.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:6]([N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[F:1])[C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:7]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCNCc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1F)C(=O)Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.554 g, 3.615 mmol) was dissolved in DMF (10 ml). (4-Hydroxyphenyl)acetic acid (0.500 g, 3.286) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (1.161 g, 3.615 mmol) and N-ethyl-N,N-diisopropylamine (0.892 g, 6.901 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.69 g of N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide (yield 73.1%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([CH:15]5[CH2:20][CH2:19][CH:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC(C(C)(C)C)CC1

Procedure:
Following General N—C coupling procedure 1 trans-7-(4-tert-butyl-cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (157 mg, 0.43 mmol), was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, which gave upon work up gave 3-{6-[7-(4-tert-Butyl-cyclohexyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester and was used as is.