Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[O:23][CH3:24].C(=O)(O)[O-].[Na+].Cl>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:8][C:7]1[C:2]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:23][CH3:24])[CH:16]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COc1cc(B(O)O)ccc1Cl
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
38.8 g (0.180 mol) of 2,3-dichloro-5-trifluoromethylpyridine, 33.5 g (0.180 mol) of 4-chloro-3-methoxybenzeneboronic acid, 0.7 g (0.61 mmol) of tetrakis(triphenylphosphine)palladium(O) and 45.3 g (0.539 mol) of sodium bicarbonate in a mixture of 550 ml of dimethoxyethane and 550 ml of water were refluxed for four hours. The mixture was then acidified to pH 4-5 with dilute hydrochloric acid, the dimethoxyethane was removed by distillation, and the remaining aqueous phase was extracted with methylene chloride. The combined methylene chloride phases were washed with water, dried over sodium sulfate and evaporated. The residue was stirred with a little cold n-hexane, filtered off with suction and dried. Yield: 44.2 g (76%) of colorless crystals of melting point 72° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].Cl.Cl.[CH:20]12CCC(NC1)CN2>>[CH:1]([N:4]1[CH2:9][CH:8]2[CH2:20][CH2:10][CH:5]1[CH2:6][N:7]2[C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)([CH3:2])[CH3:3]
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Reactant: C1CC2CNC1CN2
Agent: Cl
Product: CC(C)N1CC2CCC1CN2c1ccc(N)cc1

Procedure:
This compound is prepared according to the same procedure as described for Intermediate 7 using 2,5-diazabicyclo[2.2.2]octane dihydrochloride (J. Heterocycl. Chem, 1974, 11, 449-451).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([CH:23]4[CH2:25][CH2:24]4)[CH:30]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: NCc1cc(C2CC2)no1
Product: O=C(NCc1cc(C2CC2)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-cyclopropyl-5-isoxazolemethanamine (CAS Registry No. 851434-73-6) as starting materials; LC-MS (UV peak area/ESI) 97.6%, 452.0973 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:22]([O-])([OH:24])=[O:23]>CC(O)=O>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 94 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (7.87 g, 26.4 mmol) in AcOH (50 mL) was added HNO3 (90%, 4 mL) and the mixture was heated at 50° C. for 5 hours, to afford ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an oil (8.531 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.12 (s, 1H), 4.37 (q, 2H), 4.25 (m, 4H), 3.80 (m, 4H), 3.45 (s, 6H), 1.35 (t, 3H); LC-MS (ESI) m/z 344 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 69.6 %

Procedure:
1.80 g (5.0 mmol) of 4-[4-(tert-butoxycarbonylamino) butylamino]-3-nitroquinoline) was dissolved to a mixed solvent of 30 ml of methanol and 10 ml of ethyl acetate. 0.5 g of 10% palladium-carbon was added thereto and the mixture was stirred overnight under hydrogen atomosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 10:1 (v/v)) to obtain 1.15 g (3.48 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino]quinoline shown below as a brown amorphous substance. ##STR52## Its physicochemical properties were in agreement with those of the compound of Example 22.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC[C@H](C)[C@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21)C(=O)N(C)C

Procedure:
With 3.98 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 63-2 (15.5 mmol, crude form) as starting materials, respectively 1.28 g (Isomer A, colorless powder) and 2.60 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1N)([O-:3])=[O:2].[I:14]CI>>[I:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: ICI
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a dispersion of 2,6-dinitroaniline (4.00 g, 0.021 mol) in diiodomethane (24 mL, 0.297 mol) isoamylnitrite (15 mL, 0.112 mol) was added (Smith et al., 1990, which is incorporated herein by reference). The mixture was stirred at room temperature for one hour, and then heated at 105° C. for eight hours. The excess of diiodomethane was removed in high vacuo. The residue was diluted with acetyl acetate (10 mL). Silica (ca 30 mL, mesh 230-400 Å) was added; the mixture was concentrated in vacuo and purified by column chromatography to yield 1-iodo-2,6-dinitrobenzene (3.21 g, 52%). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, 2H, J=8.0 Hz), 7.67 (t, 1H, J=8.0 Hz).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:13][C@H:14]1[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]1)(=O)C1C=CC=CC=1.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[N+:1]([C:21]1[CH:22]=[CH:23][C:18]([C@H:16]2[CH2:15][C@H:14]([OH:13])[CH2:17]2)=[CH:19][CH:20]=1)([O-:4])=[O:2]
Reactant: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc([C@H]2C[C@H](O)C2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a mixture of nitric acid (fuming, 2.3 mL) and acetic anhydride (25 mL) was added dropwise a mixture of trans-3-phenylcyclobutyl benzoate (step 2, 3.7 g, 24.6 mmol) and sulfuric acid in acetic anhydride (25 mL) at −23° C. The resulting mixture was stirred in an ice-bath for 1.5 h. The mixture was poured into ice water (200 mL) and extracted with dichloromethane (2×100 mL). The organic layer was washed with water and brine (100 mL), then dried (Na2SO4), and concentrated. The oily residue was dissolved in methanol (100 mL), and 4N aqueous LiOH (50 mL) was added. The resulting mixture was stirred at room temperature for 10 min, then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 2.7 g (56%) of the title compound as a pale yellow oil: MS (EI) m/z 193 (M+); 1H-NMR (CDCl3) δ 8.18 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=8.6 Hz), 4.62-4.52 (1H, m), 3.81-3.71 (1H, m), 2.54-2.45 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)co2)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1coc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.56 (m, 3H), 7.34 (s, 1H), 6.64 (s, 1H), 5.31 (s, 2H), 2.60 (s, 3H); MS (ES) m/z 450 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][N:20]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][N:20]([CH2:30][C:31]([OH:33])=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)O)C1=O

Procedure:
Following the procedure described in Example 43, 0.15 g of isomer B of t-butyl α-[6-(1-butoxycarbonyl-3-phenylpropylamino)-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate (obtained as described in Example 59) was de-t-butyrated using trifluoroacetic acid, to afford 95 mg of the title compound as a powder.
Reaction SMILES: C#C.[C:3](O[K])(C)(C)[CH3:4].[CH2:9]1[CH2:19][CH:18]2[CH:12]([CH2:13][C:14]([CH2:16][CH2:17]2)=[O:15])[CH2:11][CH2:10]1>C1COCC1>[C:3]([C:14]1([OH:15])[CH2:16][CH2:17][CH:18]2[CH:12]([CH2:11][CH2:10][CH2:9][CH2:19]2)[CH2:13]1)#[CH:4]
Reactant: CC(C)(C)O[K]
Reactant: O=C1CCC2CCCCC2C1
Agent: C#C
Solvent: C1CCOC1
Product: C#CC1(O)CCC2CCCCC2C1
Reaction time: 3.5 h
Yield: 85.5 %

Procedure:
Acetylene was bubbled for 4 hours through a mixture of tBuOK (95.8 g, 0.85 mol) in THF (11) at 0° C. 2-Decalone (100 g, 0,66 mol) was added slowly at RT to the slightly yellow suspension and the resulting mixture was stirred for additional 3.5 hours, quenched with saturated NH4Cl (500 ml) solution, and extracted with MTBE (2×700 ml). The combined organic phases were washed with NH4Cl (500 ml), H2O (2×500 ml), saturated NaCl (500 ml) solution until neutral pH was achieved, dried (MgSO4), and concentrated in vacuo. The crude orange oil was flash distilled (0.01 Torr, 88-90° C.) yielding 100.6 g (86%) of 2-ethynyldecahydro-naphthalen-2-ol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[C:37]#[N:38])=[CH:4][C:5](=[O:29])[N:6]([CH:8]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[C:37]#[N:38])=[CH:4][C:5](=[O:29])[N:6]([CH:8]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CC2CC2)C(=O)Nc2ccc(C(=O)O)cc2)cc1Cl

Procedure:
192 mg (0.34 mmol) of tert-butyl 4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoate (racemate) (Example 13.1D) were hydrolysed with TFA according to General Method 2. Yield: 141 mg (82% of theory)
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:25][CH:26]=1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:25][CH:26]=1)=[C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:17]2
Reactant: COc1ccc2c(c1)CCC(Br)=C2c1ccc(OCCN2CCCC2)nc1
Reactant: [Li]c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
Phenyllithium (1.8 M in cyclohexane/ether, 3.8 mL, 7.0 mmol) was added slowly to zinc chloride (0.5 M in THF, 14 mL, 7.0 mmol) at 0° C. After stirring for 15 min, 5-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine (1.0 g, 2.3 mmol) in dry THF (20 mL) was added followed by Pd(PPh3)4 (200 mg, 0.173 mmol). The reaction was warmed to room temperature and was heated at reflux for 4 h. The reaction was poured into aqueous NH4Cl solution (satd). The aqueous layer was washed with CHCl3 (2x) and the combined organic solutions were washed with water followed by brine. The organic solution was dried (MgSO4), filtered, and concentrated in vacuo. Flash chromatography (CHCl3: MeOH, 95:5) provided the title compound (680 mg, 68%). 1H NMR (250 MHz, CDCl3): δ7.78 (d, J=2.1 Hz, 1 H), 7.27 (m, 1 H), 7.07 (m, 5 H), 6.68 (m, 4 H), 4.40 (t, J=5.8 Hz, 2 H), 3.80 (s, 3 H), 2.88 (m, 6 H), 2.71 (m, 4 H), 1.81 (m, 4 H).
Reaction SMILES: C(=O)(OCCC(N[C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:18]1)C1C=CC=CC=1F)N.Cl.[NH2:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:42]([OH:47])[C:43]([F:46])([F:45])[F:44]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:19]2[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:27])([F:26])[F:28])[C:21](=[O:22])[N:17]([CH2:16][C:15]([NH:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:42]([OH:47])[C:43]([F:44])([F:45])[F:46])=[O:37])[N:18]=2)=[CH:31][CH:32]=1
Reactant: NC(c1ccccc1)C(O)C(F)(F)F
Reactant: NC(=O)OCCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1ccccc1F
Agent: Cl
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(c1ccccc1)C(O)C(F)(F)F

Procedure:
In the same way as for the compound from Example 93, 100 mg (0.27 mmol) of the compound from Example 8A and 73 mg (0.30 mmol) of 3-amino-1,1,1-trifluoro-3-phenylpropan-2-ol hydrochloride were reacted. This gave 102 mg (63% of theory) of the target compound as a diastereomer mixture.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C=O.[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: [BH3-]C#N
Reactant: COC(=O)C(CNCc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)C(CN(C)Cc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Sodium cyanoborohydride (121 mg) was added to a solution of formaldehyde (570 mg), methyl 2-(tert-butoxycarbonylamino)-3-(3,4-dichlorobenzylamino)propionate (720 mg) and acetic acid (0.1 ml) in acetonitrile and the mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate (10 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless oil (722 mg). NMR δH (360 MHz, CDCl3) 1.45 (9H, s), 2.21 (3H, s), 2.73 (2H, d, J=7.0 Hz), 3.46 (2H, m), 3.75 (3H, s) 4.37 (1H, m), 5.19 (1H, br s), 7.10 (1H, dd, J=11.0 and 1.0 Hz), 7.36 (2H, m).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([CH2:9][C:10]#[N:11])=[O:8])([O-:14])=[O:13]
Reactant: N#CCC(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Product: N#CCC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
Benzoylacetonitrile (14.5 g, 10 mmol) was added to cold fuming nitric acid (50 ml) portionwise over 10 min. The reaction mixture was stirred for 15 min., and then poured into ice. The solid was filtered off and recrystallised from ethanol to give 2-(3-nitrobenzoyl)-acetonitrile (5.4 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[CH:14]=O)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.C(C1C=C(B(O)O)C=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][NH:31][CH3:30])[CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1
Agent: CN
Agent: O=Cc1cccc(B(O)O)c1
Product: CNCc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1

Procedure:
3-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (247 mg, 0.80 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-etrahydro-azepino[5,4,3-cd]indol-6-one and 3-formylphenylboronic acid) was reacted with methylamine (4.91 mmol) as described for Compound PPP to yield 8-fluoro-2-(3-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 193 mg (74%) as an off-white solid: m.p. 270-272° C. (dec); 1H NMR (300 MHz, d6-DMSO) 2.34 (s, 3H), 3.05 (m, 2H), 3.39 (m, 2H), 3.78 (s, 2H), 7.42 (m, 5H), 7.61 (br s, 1H), 8.26 (br t, 1H), 11.70 (br s, 1H). HRMS (MALDI, MH+) Calcd for C19H18N3OF: 324.1512. Found: 324.1498. Anal. (C19H18N3OF.1.5 H2O.0.35 CHCl3) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.FC(F)(F)S(O[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH2:18][C@H:19]([N:26]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][O:21]2)(=O)=O>>[CH2:34]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:19]1[CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[O:21][CH2:20]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: OB(O)c1cncnc1
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cncnc4)c3C2)cc1
Yield: 78 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 78% yield, starting from 5-pyrimidinylboronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro -2H-chromen-5-yl trifluoromethanesulfonate; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1 H), 8.86 (s, 2 H), 7.24-7.34 (m, 8 H), 7.15-7.23 (m, 3 H), 6.86 (d, 2 H), 4.32-4.38 (m, 1 H), 4.00-4.08 (m, 1 H), 3.61-3.75 (m, 4 H), 3.05-3.14 (m, 1 H), 2.93-3.03 (m, 1 H), 2.46-2.54 (m, 1 H, obscured by DSMO); MS (ESI) m/z 408[M+H+].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3C2CCCCO2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH2:33]([NH2:35])[CH3:34].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>C1COCC1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:33]([NH:35][C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][NH:21]3)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1)[CH3:34]
Reactant: CCN
Reactant: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: C1CCOC1
Product: CCNc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A solution of 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.200 g, 0.443 mmol) and ethylamine (0.553 mL, 1.106 mmol) (Aldrich, St. Louis, Mo.) in THF (10 mL) was treated with sodium tert-butoxide (0.128 g, 1.328 mmol) and 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (0.030 g). The mixture was deoxygenated and treated with Pd2(dba)3 (0.041 g, 0.044 mmol) under N2. The flask was fitted with a reflux condenser, then placed into a pre-heated bath at 80° C. and stirred overnight. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with NaHCO3 (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a tan oil. A glass microwave reaction vessel was charged with the crude oil and 1 N aqueous HCl (1.5 mL) in THF (3 mL). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 8 min (100 watts, Powermax feature on). The mixture was concentrated and neutralized with SiliCycle Si-Carbonate Silica Gel (SiliCycle Inc., Quebec City, Canda) (0.800 g). The mixture was diluted with THF (5 mL) and allowed to stir under inert atmosphere overnight. The mixture was concentrated, diluted with DCM (10 mL) and filtered. The desired product was released from the silica by rinsing with methanol (20 mL). The filtrate was concentrated and triturated with diethyl ether to give N5-ethyl-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridine-2,5-diamine (0.065 g, 0.173 mmol, 39.0% yield) as a tan solid. MS (ESI pos. ion) m/z 377 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.65 (d, 1H); 8.35 (d, 1H); 8.20 (s, 1H); 7.92 (d, 1H); 7.76 (s, 1H); 6.75 (d, 1H); 3.87 (s, 3H); 3.20 (m, 2H); 2.80 (s, 3H); 1.29 (s, 3H).