Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[N:27]1[N:28]=[C:29]([NH:32][CH:33]2[CH2:36][CH:35]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[CH2:34]2)[NH:30][CH:31]=1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:18])[N:32]([CH:33]3[CH2:34][CH:35]([C:37]([O:39][CH2:40][CH2:41][CH3:42])=[O:38])[CH2:36]3)[C:29]3[N:28]([N:27]=[CH:31][N:30]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CCCOC(=O)C1CC(Nc2nnc[nH]2)C1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCOC(=O)C1CC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)C1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (12 g), propyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (4 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) and N,N-diethylaniline (50 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a mixture of geometric isomers (5 g, 55%).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]2[CH3:24])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCCC2C)ncn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 2-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. and 3 hours at 120° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 66 mg of 4-(2-butynyloxy)-6-(2-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (20)).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15][CH2:16]B(O)O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:15][CH2:16][C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(Br)s1
Reactant: OB(O)CCC1CCCCC1
Product: O=Cc1ccc(CCC2CCCCC2)s1
Yield: 57.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and 2-cyclohexylethylboronic acid (337 mg, 2.16 mmol) in place of hexylboronic acid to give 5-(2-cyclohexylethyl)thiophene-2-carbaldehyde (168 mg, 58%). Used without further characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH3:32].[I-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (215 mg, 1.00 mmol) was dissolved in tetrahydrofuran (5 mL). While this solution was chilled in an ice bath, 60% sodium hydride in oil (44.0 mg, 1.10 mmol) was added and the mixture was stirred for 20 min. Subsequently, 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (258 mg, 1.00 mmol) in tetrahydrofuran (5 mL) and sodium iodide (15.0 mg, 0.100 mmol) were added. The mixture was stirred for 2 hours while chilled in an ice bath and was further stirred for 6 hours at room temperature. Subsequently, ethyl acetate was added and the mixture washed sequentially with 5% aqueous citric acid and brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 258 mg (59%) of the desired compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(S[CH2:4][C:5]1[NH:6][C:7]([CH3:27])=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C>CO>[CH3:4][C:5]1[NH:6][C:7]([CH3:27])=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1=C(CSCC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1

Procedure:
Under nitrogen atmosphere and stirring, a MeOH solution (15 ml) of g 0.85 of (+)2-ethylthiomethyl-3-carboethoxy-5-carbomethoxy-4-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine, cooled at 30° C. is treated with NaH2PO4 (g 1.45) and with Na/Hg amalgam (2.64 g) (10% in Na). After 15 minutes the solution is filtered and evaporated to a small volume under vacuum. The residue is partitioned between water (ml 20) and AcOEt (3×30 ml), the organic phases are collected to give after the usual work-up 0.56 g of (+)-2,6-dimethyl-4-(3-chlorophenyl)-3-carboethoxy-5-carbomethoxy-1,4-dihydropyridine [α]D =+5.5°; c=4.1 CH2Cl2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[N:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:26]([C:23]2[N:24]=[N:25][C:20]([N:17]3[CH2:16][CH2:15][N:14]([C:12](=[O:13])[C:11]4[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=4[C:9]([F:34])([F:33])[F:8])[CH2:19][CH2:18]3)=[CH:21][CH:22]=2)=[O:27])[N:2]=1
Reactant: Nc1cccnn1
Reactant: O=C(Cl)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1cccnn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 28, making variations only as required to use pyridazin-3-ylamine in place of 2-aminopyridine to react with 6-[4-(2-trifluoromethylbenzoyl)-piperazin-1-yl]pyridazine-3-carbonyl chloride, the title compound was obtained as a white powder (17.3% yield). 1H NMR (300 MHz, CDCl3) δ 10.81, 9.05, 8.70, 8.13, 7.87-7.57, 7.39, 6.95, 4.16-3.80, 3.40. 13C NMR (300 MHz, CDCl3) δ 167.7, 162.3, 160.1, 148.6, 144.1, 132.4, 129.6, 128.1, 127.2, 126.9, 118.3, 112.1, 43.4, 44.6, 44.3, 41.3. MS (ES+) m/z 458.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][O+](C)C>C(Cl)Cl>[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][N+:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[O:2][CH3:1]
Reactant: C[O+](C)C
Reactant: COc1ncccn1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1nccc[n+]1C

Procedure:
Starting material prepared by reaction of 2-methoxypyrimidine with trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 4 hours to give 1-methyl-2-methoxypyrimidinium tetrafluoroborate.
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][C:11]([Cl:17])=[C:10]([CH3:18])[C:9]=1[Br:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>O.C1(C)C=CC=CC=1.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>[Br:19][C:9]1[C:8]([C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=2)=[C:13]([C:14](=[O:16])[CH3:15])[CH:12]=[C:11]([Cl:17])[C:10]=1[CH3:18]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
To a solution of sodium hydrogenecarbonate (2.8 g, 34 mmol) in water (70 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (6.7 g, 17 mmol) in toluene (70 mL) followed by (3,5-difluorophenyl)boronic acid (2.9 g, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.98 g, 0.85 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered, concentrated and purified on silica gel (eluting with 0-15% of ethyl acetate in hexanes) to give the desired product (5.6 g). LCMS calculated for C15H11BrClF2O (M+H)+: m/z=359.0. found: 359.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[NH2:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:9])[C:2]=1[Cl:1]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cccc(Oc2ncnc(N)c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 20-mL microwave vial was placed 5,6-dichloropyrimidin-4-amine (500.00 mg; 3.05 mmol), cesium carbonate (1.49 g: 4.57 mmol), and 3-aminophenol (499.08 mg; 4.57 mmol) suspended in DMF (12.00 ml). The reaction mixture was run in the microwave at 160° C. for 2 hours. The reaction mixture was allowed to cool to rt. The mixture was then filtered through a plug of silica gel. The solution was concentrated under reduced pressure and then lyophilized overnight to afford 6-(3-aminophenoxy)-5-chloropyrimidin-4-amine as a black solid crude.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(=O)C(F)(F)F)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Li+]>CN(C=O)C>[N:18]([CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)OC[C@@H]1CCCN1C(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a flask protected by a safety screen, a solution of the product of step B (12.27 g, 0.042 mmol) and lithium azide (2.47 g, 0.051 mmol) in DMF (30 ml) was stirred at 45° C. for 18 hr. The solvent was evaporated in vacuo and the residue triturated with EtOAc (100 ml) and filtered. The filtrate was evaporated in vacuo and the residue dissolved in MeOH (255 ml) which was saturated with gaseous ammonia at 0° C. and then stirred at room temperature for 72 hr. The solvent was removed by distillation in vacuo to afford the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9](Cl)[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[S:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1cc(Br)ncc1C(Cl)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 2-bromo-5-[chloro(2,5-difluorophenyl)methyl]-4-methylpyridine (6.44 g, 19.4 mmol) in N,N-dimethylformamide (100 ml), 4-fluorobenzenethiol (2.06 ml, 19.4 mmol), and then potassium carbonate (2.94 g, 21.3 mmol) were added in an argon atmosphere, at 0° C., and the mixture was stirred for 1 hour at room temperature. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and then the organic layer was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution of hexane:ethyl acetate=30:1 was concentrated under reduced pressure, to obtain the title compound (8.20 g, 19.3 mmol, 100%) as a pale brown solid.
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][NH:17][S:16]1(=[O:22])=[O:21])[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:16]1(=[O:22])=[O:21])[CH2:9]2
Reactant: O=C(CN1CCCNS1(=O)=O)NC1C2CC3CC(C2)CC1C3
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCN(CCc2ccccc2)S1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
To N-(adamantan-2-yl)-2-(1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide hydrochloride (50 mg, 0.135 mmol) in DMF (1 mL), were added K2CO3 (93.3 mg, 0.675 mmol) and (2-bromoethyl)benzene (50 mg, 0.27 mmol). The reaction mixture was agitated for 4 hr at room temperature and extracted with ethyl acetate and brine. The organic layer was dried over MgSO4 and the residue was purified by silica gel column chromatography to yield N-(adamantan-2-yl)-2-(1,1-dioxido-6-phenethyl-1,2,6-thiadiazinan-2-yl)acetamide (8 mg, 13%, white solid). 1H NMR (300 MHz, DMSO-d6): δ 7.33-7.19 (m, 5H), 7.01-6.98 (brd, 1H), 4.06-4.047 (m, 1H), 3.71 (s, 2H), 3.53-3.49 (m, 2H), 3.38-3.33 (m, 4H), 2.94-2.87 (m, 2H), 1.92-1.60 (m, 14H).
Reaction SMILES: [C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=4)[C:11]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:70]([C:72]1[CH:77]=[CH:76][N:75]=[CH:74][CH:73]=1)=[CH2:71]>C(N(CC)CC)C>[C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([CH:71]=[CH:70][C:72]5[CH:77]=[CH:76][N:75]=[CH:74][CH:73]=5)=[CH:15][CH:16]=4)[C:11]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: C=Cc1ccncc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(C=Cc3ccncc3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Yield: 59.45 %

Procedure:
N,N-diphenyl-7-bromo-9,9-di-n-decyl-9H-fluorene-2-amine (8.08 9,11.66 mmol), tri-o-tolylphosphine (1.42 g, 4.67 mmol), triethylamine (30 ml, degassed with nitrogen for 15 minutes), 4-vinylpyridine (2.52 ml, 23.32 mmol) and palladium(Il) acetate (0.13 g, 0.58 mmol) were added to a single-necked round bottom flask equipped with a magnetic stirrer and reflux condenser. The solution was heated at reflux by means of an oil bath under nitrogen for 16 hours. The solvent was removed under reduced pressure and the residue dissolved in methylene chloride. The organic layer was washed 3 times with water, dried over anhydrous MgSO4, filtered and concentrated. The product was purified by column chromatography using silica gel and 85:15 hexane:ethyl acetate to afford a yellow oil in 59.45% yield. The oil, upon standing for several days, gradually solidified to give a waxy solid (mp 88.4° C.-89.3° C.). Mass Spec. m/z 716 (M+), 576, (M-C10H20), 358 (M++). Elemental Analysis: Calculated for C52H64N2 : C, 87.10; H, 9.00; N, 3.90. Found: C, 87.17; H, 9.45; N, 3.35.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cncc(F)c1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 105.7 %

Procedure:
A mixture of (5-fluoro-2-nitro-phenyl)-(5-fluoropyridin-3-yl)amine (425 mg, 1.69 mmol) in EtOAc (30 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (50 mg) and was stirred at RT under a hydrogen atmosphere for 19 h. The mixture was filtered and the filtrate concentrated in vacuo to afford the title compound as a brown solid (395 mg, quantitative). LCMS (Method C): RT 2.24 min [M+H]+ 222.07
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:21])=[CH:23][CH:24]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccc2cccnc2c1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 21 mmol) and 4-tert -butylbenzoic acid (45 mg, 0.25 mmol) as a yellow solid. MS(ES): MH+ 305, M-H+ 303
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[O:41][N:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[O:41][N:40]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J12) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert.-butyl ester (Example K15) according to the general procedure M. Obtained as a yellow foam (522 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: CO
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(OC)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 285(MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12]([NH2:14])=[O:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>O1CCOCC1.[Cu](I)I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:14][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: NC(=O)c1c(F)cccc1F
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Br)cn1)c1c(F)cccc1F
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a mixture of 2-chloro-5-bromopyridine (370 mg, 1.9 mmol, 1.2 eq) and 2,6-difluorobenzamide (250 mg, 1.5 mmol, 1.0 eq) in dioxane (10 mL), copper iodide (151 mg, 0.75 mmol, 0.5 eq), potassium phosphate (670 mg, 3.15 mmol, 2.1 eq) and N,N-dimethylethylene diamine (0.1 mL, 1.05 mmol, 0.7 eq) were added sequentially. The resulting mixture was stirred at reflux for 15 h. The reaction was cooled to room temperature, filtered to remove the solid components and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate and hexane) to afford 300 mg of the solid product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H, D2O exchangeable), 8.70 (d, J=2.5 Hz, 1H), 8.18 (dd, J=8.0, 2.5 Hz, 1H), 7.67-7.59 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 313, 315 [(MH)+ Br79,81].
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)nc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)nc1

Procedure:
To a degassed stirred solution of 2,8-dimethyl-5-(5-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (110 mg, 0.349 mmol) in MeOH (5 mL) was added Pd/C (40 mg, 35% w/w) and purged the reaction mixture with H2 gas at RT for 2 h. The progress of reaction was monitored by TLC and NMR. Reaction mass was filtered through a Celite bed washed with MeOH (3×5 mL). Filtrate was concentrated under reduced pressure and residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(5-methyl-pyridin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.42 (s, 1H), 8.02 (d, 1H), 7.48 (d, 1H), 7.21 (s, 1H), 7.12 (d, 1H), 6.98 (d, 1H), 4.67 (d, 1H), 4.5 (t, 2H), 4.3 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.38 (t, 2H), 3.1 (m, 5H), 2.41 (s, 3H), 2.39 (s, 3H).