Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1.[O-]CC.[Na+].[CH3:21][C:22]([CH:24]=[CH2:25])=[O:23].Cl>C(O)C>[O:23]=[C:22]1[CH2:24][CH2:25][C:3]2[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=2[CH2:21]1
Reactant: O=C1Cc2ccccc2Oc2ccccc21
Reactant: C=CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
To a solution of 42 g of the compound 10-keto-10,11-dihydro-dibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of sodiumethoxide (7 g of sodium in 500 ml of ethanol) is added dropwise. After stirring the mixture for 30 minutes 16.2 ml of methylvinylketon in 50 ml of ethanol are added, whereupon the solution is refluxed for 1 hour. The solution is cooled then and poured into 2 N HCl. After extracting into ether, washing the ether layer with water (till neutral) and drying the etherial phase, the solvent is evaporated.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:26])([F:27])[O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:20][CH:21]=1
Reactant: NCCCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.460 g, 2.0 mmol), 3-(4-trifluoromethoxy-phenyl)-propylamine (0.438 g, 2.0 mmol), and K2CO3 (0.500 g, 3.6 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-trifluoromethoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.248 g, 37%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.97 (m, 2H), 2.70 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.09 (d, 2H), 7.23 (t, 2H), 7.42-7.56 (m, 3H), 7.86 (d, 1H). GC-MS: m/z 335 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(Br)c1
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Combine 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 3, 0.986 g) in DMF (10 mL) and add to a suspension of sodium hydride (95%, 0.127 g) in DMF (10 mL) and heat in an oil bath at 65° C. After 30 min., add 1-bromo-3-fluoro-benzene (0.96 g) and heat at 65° C. After 18 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:9) to give the title compound as a colorless oil (0.759 g). 1H NMR (CDCl3): 7.13 (dd, 1H), 7.05 (ddd, 1H), 7.04 (m, 1H), 6.81 (ddd, 1H), 4.63 (m, 1H), 4.35 (m, 1H), 3.88 (m, 1H), 3.23 (m, 1H), 1.90 (m, 3H), 1.73 (m, 1H), 1.46 (s, 9H), 1.27 (d, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:12]=[C:13]([OH:20])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])([O-:10])=[O:9].Cl.O1CCOCC1.[OH-].[Na+]>CCOC(C)=O.Cl.O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:20][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([O-:10])=[O:9]
Reactant: Clc1ccncc1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccncc2)cc1[N+](=O)[O-]
Temperature: 145 °C
Reaction time: 0.75 h

Procedure:
4-Chloropyridine (3.20 g, 28.2 mmol) and 3,4-dinitrophenol (5.96 g, 32.4 mmol) were combined in an open round-bottom flask fitted with running water condenser. The reaction flask was heated to 145° C. After 45 min, 4N HCl/dioxane (2.1 mL) was added. The reaction was heated for an additional 25 min then cooled to RT. The mix was dissolved in EtOAc and 0.5 N HCl/water. The aqueous layer was basified with 6 N NaOH. A beige solid was isolated and identified as title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([N:16]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[CH:18]=[C:17]1B(O)O)(OC(C)(C)C)=O>>[F:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:16][C:17]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:7]=1)=[CH:18]2
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(F)ccc21
Reactant: Fc1cncc(Br)c1
Product: Fc1cncc(-c2cc3cc(F)ccc3[nH]2)c1

Procedure:
3-Fluoro-5-bromopyridine and N-Boc-5-fluoro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 5-fluoro-2-(5-fluoro-pyridin-3-yl)-1H-indole. (ESI) m/z 231.04 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:15])=[O:14]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:19][CH:18]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Reactant: Nc1nc2c(Br)cccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CS(=O)(=O)Cc1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
A suspension of (4-bromomethylphenyl)boronic acid (2.0 g, 9.3 mmol) and sodium methanesulfinate (1.4 g, 14 mmol) in Ethanol (30 mL) was heated at 60° C. for 24 hours. The mixture was evaporated to dryness and the residue was suspended in water. The precipitate was filtered, rinsed with water and air dried. The reaction product was isolated as an off-white solid (1.18 g, 59%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.09 (s, 2H), 7.79 (d, J=7.9 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 4.47 (s, 2H), 2.88 (s, 3H). MS=135 (M—SO2CH3)+. 48b) 8-(4-Methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200.0 mg, 0.9388 mmol) and (4-methanesulfonylmethylphenyl)boronic acid (240.0 mg, 1.121 mmol) with Pd(dppf)Cl2 (130.0 mg) as the catalyst in a manner analogous to Step 2c. The reaction product was isolated as a pale yellow solid (0.051 g, 18%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.56 (dd, J=6.6, 1.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 2H), 7.73 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 6.99 (dd, J=7.3, 7.3 Hz, 1H), 6.11 (s, 1H), 4.55 (s, 2H), 2.94 (s, 3H). MS=303 (MH)+. 48c) [8-(4-Methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.165 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (51.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.009 g, 11%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44-8.40 (m, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.60-7.54 (m, 3H), 7.51-7.46 (m, 2H), 7.00-6.93 (m, 3H), 6.70 (s, 1H), 4.32 (s, 2H), 3.21-3.14 (m, 4H), 2.83 (s, 3H), 2.66-2.56 (m, 4H), 2.37 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:23])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:24]([S-:26])#[N:25].[K+].BrBr>CC(O)=O.C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]2[N:22]=[C:24]([NH2:25])[S:26][C:17]=2[C:16]=1[Br:23])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: N#C[S-]
Reactant: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: BrBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2nc(N)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C (1.5 g), attached with a balloon of H2. More Pt/C (500 mg) was added after 3 h. Then the reaction mixture was stirred at rt for another 2 h. The reaction mixture was filtered over celite, concentrated down to give product (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) and went to next step without purification. To a solution of (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) (21.63 mmol) in HOAc/THF (80 ml, 1:1) was added KSCN at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then Br2 was added slowly, reacted at 0° C. The reaction was quenched by adding sat. NaHSO3, extracted by EtOAc, dried over MgSO4, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65H (2.3 g, 24% over 2 steps).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:15]([F:29])[CH:14]=2)[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC[N:43]([CH:47]([CH3:49])[CH3:48])C(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH:47]1([NH:43][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])=[C:15]([F:29])[CH:14]=3)[N:3]=2)[CH2:49][CH2:48]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)N2CCOCC2)c(F)cc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCOCC2)c(F)cc1Nc1ncc(C(F)(F)F)c(NC2CC2)n1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
To a solution of (4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)-(morpholino)methanone (120 mg, 0.28 mmol) in dioxane (2 mL) was added pTSA (52 mg, 0.28 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol). The mixture was heated to 100° C. for 2 hours. LSMS of crude sample indicated only 10% of desired material. DIPEA (100 μL, 0.56 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol) were added and the mixture was heated to 100° C. for one hour. After return to room temperature, DCM (20 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were added. The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by reversed phase HPLC to give (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)-methanone (42 mg, 33%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=460 at 3.41 min. 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J=12.8 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=5.6 Hz, 1H), 5.48 (s, 1H), 3.92 (s, 3H), 3.80-3.74 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.43 (m, 2H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](O)(=[O:25])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1>ClCCl>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)O
Reactant: Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(Nc2nccc(Sc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a stirred solution of N1-(4-(phenylthio)pyrimidin-2-yl)benzene-1,3-diamine (80 mg, 0.27 mmol) and acrylic acid (37 μL, 0.54 mmol) in anhydrous dichloromethane (2 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride salt (78 mg, 0.41 mmol), triethylamine (114 μL, 0.82 mmol) and 4-pyrrolidinopyridine (5 mg). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. It was diluted with dichloromethane (20 mL), washed with water, 2.0 M aqueous sodium carbonate solution, and dried (Na2SO4). After removal of the solvent in vacuo, the residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (50:50→100:0) as eluant to give the desired product (31 mg, 33%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([NH:29][C:26]2[CH:27]=[N:28][C:23]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:24][CH:25]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CN1C(=O)C(Nc2ccc(N3CCOCC3)nc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 6-morpholin-4-ylpyridin-3-amine in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 3.20 (s, 3H), 3.26-3.30 (m, 4H), 3.65-3.70 (m, 4H), 6.31 (d, 1H), 6.94-6.99 (m, 1H), 7.11-7.22 (m, 4H), 7.25-7.30 (m, 1H), 7.58 (bs, 1H), 7.71 (d, 1H); Mass Spectrum: M−H+ 399.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CNCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 260C (1.01 g, 2.58 mmol) in dichloromethane (50 mL) at 0° C. was treated with TFA (5 mL). The reaction mixture was stirred at 0° C. for 1.0 hour then allowed to slowly warm to room temperature and stirred for an additional 2.0 hours. The mixture was concentrated, and then azeotropically evaporated with MeOH and toluene. The residue was dissolved in dichloromethane and washed with saturated NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 0.61 g (yield: 81%) of Compound 260D as an oil. It was used in the next step without further purification.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH2:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[CH:14]=[CH:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:13]([N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:3](=[O:4])[CH:2]([Br:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH:14]=[CH:15][CH3:16]
Reactant: O=C(Cl)C(Br)c1ccc(F)cc1
Reactant: CC=CCNc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CC=CCN(C(=O)C(Br)c1ccc(F)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
In 40 ml of toluene, 2.6 g of 2-bromo-2-(4-fluorophenyl)acetyl chloride were gradually added dropwise at 20°-30° C. under stirring to 2.2 g of N-(2-butenyl)-N-(3-trifluoromethylphenyl)amine. After the reaction mixture was stirred for further 20 minutes, the precipitated insoluble matter was filtered off and 50 ml of toluene were added. The resulting toluene solution was washed twice with a saturated aqueous solution of sodium bicarbonate and twice with saturated saline. The toluene solution was dried over anhydrous sodium sulfate and then concentrated in an evaporator, whereby the intended compound was stoichiometrically obtained in an oily form.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]2[C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[F:52])[NH2:48]>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.O1CCOCC1.CC(O)(C)C>[Cl:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[F:52])[NH:48][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]2[C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
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: CC(C)(C)O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(Nc4ccc(F)c(Cl)c4)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Yield: 47.8 %

Procedure:
A suspension of 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (106 mg, 0.20 mmole), K2CO3 (62 mg, 0.45 mmole) and 3-chloro-4-fluoroaniline (60 mg 0.40 mmole) in a 1,4-dioxane/t-BuOH 5:1 mixture (2 ml) was purged with nitrogen for 15 minutes. Thereafter, tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 μmol) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 20 hours. Upon cooling, the mixture was partitioned between ethyl acetate and brine. The organic phase was evaporated under reduced pressure and the crude residue was purified by flash chromatography on silica, using an ethyl acetate/n-hexane mixture as the mobile phase (in a ratio gradually ranging from 1:1 to 4:1), thus affording the pure title compound (60 mg, yield 47%) which was characterized by its mass spectrum as follows: MS (m/z): 628 ([M+H]+, 100).
Reaction SMILES: [C@H:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CC[CH2:2]1.Cl.Cl.Cl.NC1CCN(C[C@@H]([N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)C)CC1>>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([C@@H:1]([CH3:2])[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:16][CH2:17]2)[CH2:57][CH2:58]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120, see example 86) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15]CC3C=CC(OC)=CC=3)[CH2:9]2)=[CH:6][C:5]([C:25]#[N:26])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([N:34]([CH:44]2[CH2:46][CH2:45]2)CC2C=CC(OC)=CC=2)[C:31]2=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]2[N:29]=1.C(N(CC)CC)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[N:33]=[C:32]([NH:34][CH:44]3[CH2:46][CH2:45]3)[C:31]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]3[N:29]=2)=[CH:4][C:5]([C:25]#[N:26])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][S:60]([CH3:59])(=[O:62])=[O:61])[CH2:9]1
Reactant: COc1ccc(CNCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCO2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCC1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Temperature: 25 °C

Procedure:
To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(((4-methoxybenzyl)amino)methyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38.9 mg, 0.055 mmol) in tetrahydrofuran (276 μl) was added triethylamine (13.84 μl, 0.099 mmol) and methanesulfonyl chloride (5.59 μl, 0.072 mmol). The reaction mixture was stirred at room temperature ON. The reaction mixture was diluted with ethyl acetate and transferred to a separatory funnel containing saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was taken forward into the deprotection.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([C:10](O)=O)[CH2:6]2)OCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[C:27](=[O:40])[N:28]([CH2:37][CH2:38][CH3:39])[C:29](=[O:36])[N:30]([CH2:33][CH2:34][CH3:35])[C:31]=1[NH2:32]>C(Cl)Cl>[CH2:37]([N:28]1[C:27](=[O:40])[C:26]2[NH:25][C:10]([CH:7]3[CH2:8][CH2:9][C:5](=[O:1])[CH2:6]3)=[N:32][C:31]=2[N:30]([CH2:33][CH2:34][CH3:35])[C:29]1=[O:36])[CH2:38][CH3:39]
Reactant: O=C(O)C1CCC2(C1)OCCO2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
2.4 g (0.014 mol) of 1,4-dioxaspiro[4,4]nonan-7-carboxylic acid are dissolved in 56 ml of methylene chloride and after the addition of 2.2 g (0,014 mol) of carbonyldiimidazole stirred for 1 hour at ambient temperature. Then 3.2 g (0,014 mol) of 5,6-diamino-1,3-dipropyluracil are added and the mixture is stirred for a further 4 hours at ambient temperature. The solution is evaporated down in vacuo, the oily residue is mixed with 70 ml of water and 4.5 g of Ca(OH)2 and stirred for 1 hour at 70° C. 100 ml of 50% NaOH are added, the mixture is stirred for a further hour at 70° C. and for 16 hours at ambient temperature. Whilst being cooled with ice, the solution is adjusted to pH 6 with HCl and extracted with methylene chloride. After drying and evaporation in vacuo the combined organic phases yield a crystalline residue which is recrystallised from ethanol using activated charcoal. 0.8 g (16%) of white crystals are obtained, m.p. 147°-148° C.