Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1ccccc1O)NCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Chlorophenoxyethyl)-3-(2-methoxyphenyl)propanamide (12.8 g, 38.3 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, a 1.0M-boron tribromide/methylene chloride solution (49.8 mL, 49.8 mmol) was slowly added dropwise thereto under ice-cooling, followed by stirring for 1 hour at room temperature. Subsequently, water was slowly added dropwise thereto under ice-cooling, followed by stirring for 30 minutes. The resultant mixture was extracted with chloroform. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (11.6 g, 95%).
Reaction SMILES: [F:1][C:2]1([F:20])[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([N:4]1[CH2:3][C:2]([F:1])([F:20])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1)[C:29]#[C:30][CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 65.4 %

Procedure:
To a mixture of crude tert-butyl 10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (65.0 mg, 0.222 mmol) and K2CO3 (61.5 mg, 0.445 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-bromobut-2-yne (29.2 μL, 0.334 mmol) and the reaction heated at 45° C. for 48 h. The reaction was diluted with ethyl acetate and filtered. The filtrate was dried over Na2SO4, filtered and concentrated. Silica gel chromatography (4 g silica, 1-100% ethyl acetate/hexane) provided tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 65%) as a colorless oil. ESI-MS m/z calc. 344.2. Found 345.3 (M+1)+; Retention time: 1.91 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 3.80 (br s, 2H), 3.35 (q, J=2.2 Hz, 2H), 3.23 (t, J=12.1 Hz, 2H), 2.80 (t, J=8.5 Hz, 2H), 2.48 (s, 2H), 2.02 (d, J=13.2 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.54-1.48 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:11])=[C:7]([CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCC2)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Into a round-bottom flask, was placed a solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 490 mg, 1.57 mmol, 1.00 equiv, 70%) in N,N-dimethylformamide (8 mL). Compound 1.5 (500 mg, 1.57 mmol, 1.00 equiv), EDC.HCl (860 mg, 4.26 mmol, 2.00 equiv, 95%) and 4-dimethylaminopyridine (550 mg, 4.28 mmol, 2.00 equiv, 95%) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature, and then diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 4×30 mL of brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to yield 560 mg (74%) of the title compound as a white solid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:45])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([F:29])[CH:23]=3)=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:9][CH:8]=1.C1CCN2[C:51](=[N:52][CH2:53]CC2)CC1.CNC>O1CCCC1>[CH3:51][N:52]([CH3:53])[C:5](=[O:45])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([F:29])[CH:23]=3)=[O:30])=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1F
Reactant: C1CCC2=NCCCN2CC1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)N(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1F
Temperature: 60 °C
Yield: 87.5 %

Procedure:
The product of Example 105B (0.108 g, 0.15 mmol) in tetrahydrofuran (3 mL) was treated with DBU (0.023 g, 0.15 mmol) and Dimethylamine (2.0 M in THF, 0.75 mL, 1.5 mmol) and heated at 60° C. for 20 minutes in a sealed tube, cooled, and concentrated under vacuum. The resulting residue was purified by chromatography on silica eluting with 97:3 dichloromethane/methanol to provide the title compound (0.08 g, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H), 2.19 (s, 3 H), 2.93 (s, 6 H), 3.15-3.29 (m, 1 H), 7.01 (d, J=8.46 Hz, 1 H), 7.23 (t, J=8.64 Hz, 1 H), 7.33 (d, J=8.46 Hz, 2 H), 7.43 (dd, J=8.27, 1.65 Hz, 1 H), 7.57 (d, J=8.82 Hz, 2 H), 7.62-7.71 (m, 2 H), 7.80 (dd, J=8.27, 1.65 Hz, 1 H), 7.99 (s, 1 H), 8.50 (s, 1 H), 8.60 (s, 1 H), 8.87 (d, J=8.46 Hz, 1 H), 10.22 (s, 1 H), 10.30 (s, 1 H); MS (ESI+) m/z 610 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[C:22]([F:27])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[C:22]([F:27])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])[C:12]=1[F:31])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2[N+](=O)[O-])c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(5-cyano-4-fluoro-2-nitrophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (78.0 mg, 0.085 mmol) in DCM (7 ml) was added TFA (3.0 mL) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(5-cyano-4-fluoro-2-nitrophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (39 mg, 0.083 mmol, 98% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.14 (d, 1H), 7.75 (s, 1H), 7.27-7.50 (m, 3H), 4.64 (s, 2H). LC-MS (ES+) m/z 468.07, [M+H].
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.[CH3:20][CH:21]([CH3:25])[C:22](Cl)=[O:23]>C1COCC1.CCCCCC>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:22](=[O:23])[CH:21]([CH3:25])[CH3:20]
Reactant: COCOc1cccc(OCOC)c1
Reactant: CC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cccc(OCOC)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
1,3-bis{[(methyloxy)methyl]oxy}benzene (Intermediate 35, 2.2 g) was dissolved under nitrogen in THF (8.0 mL) and a solution of BuLi (8.32 mL of a 1.6 M solution in hexane, 13.3 mmol) was added. After stirring at room temperature for 1 hour, cooling down to −78° C., 2-methylpropanoyl chloride (4.65 ml, 44.4 mmol) was added and the reaction mixture was stirred at that temperature for 1 hour. After quenching with water, the reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was then charged on a silica gel column (Biotage SP1 system) and eluted with Cyclohexane/EtOAc (from all 10/0 to 9/1, then 9/1, then from 9/1 to 8/2, then 8/2) to afford the title compound (825 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([Br:10])=[CH:12][C:13]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)c1ccccc1
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Yield: 19.8 %

Procedure:
The procedure was in the same manner as described in example 15, except that the starting material was benzoic acid instead of p-chlorobenzoic acid and 4-bromoaniline instead of 4-chloroaniline. The title compound was obtained as yellow needle crystal, and yield 19.8%, m.p.109-110° C.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1.Br[CH2:20][CH2:21][F:22].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:22][CH2:21][CH2:20][O:18][C:14]1[CH:13]=[C:12]([C:10]2[N:11]=[C:5]3[N:4]=[C:3]([NH2:2])[CH:8]=[CH:7][N:6]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FCCBr
Reactant: Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 70 °C
Reaction time: 23 h
Yield: 21.2 %

Procedure:
In a sealed tube 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (800 mg, 2.6 mmol) was combined with DMF (4.0 ml) to give a light brown solution. 1-Bromo-2-fluoroethane (476 mg, 3.75 mmol) dissolved in DMF (4.0 ml) and Cs2CO3 (1.62 g, 4.97 mmol) were added. The reaction mixture was stirred 23 h at 70° C. H2O (50 ml) was added to the reaction mixture and the product was extracted with EtOAc (3×40 ml). After drying over MgSO4, filtration and concentration in vacuum, the crude product (orange oil) was purified by flash chromatography (50 g SiO2—NH2 cartridge, eluent: CH2Cl2 to CH2Cl2/MeOH 95:5) to yield the title compound (150 mg, 21%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1.[H-].[Na+].Cl[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][N:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[N:18][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:8]=3)=[N:14][CH:15]=2)[CH:23]=[N:22]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: COCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1cc(-c2cnc(-c3cccc(-c4cnn(C)c4)c3)nc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 130 mg; 0.43 mmol; 1.0 eq.) in dry DMF (1 mL) was added over a suspension of NaH (60% in oil, 21 mg; 0.86 mmol; 2.0 eq.) in dry DMF (1 mL) maintained at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0° C. then heated at 100° C. O/N after the addition of a solution of 1-chloro-3-methoxypropane (47 mg; 0.43 mmol; 1.0 eq.) in DMF (2 mL). Reaction mixture was then cooled down to RT, quenched with water and extracted with EtOAc (three times). Combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting solid was dried O/N at 60° C. under reduced pressure to give the title compound a beige powder (165 mg; 75%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.58-8.49 (m, 1H), 8.46 (s, 1H), 8.30-8.17 (m, 2H), 8.17-8.11 (m, 1H), 7.96-7.89 (m, 1H), 7.75-7.68 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.22 (t, J=7.0 Hz, 2H), 3.90 (s, 3H), 3.39-3.30 (m, 2H), 3.25 (s, 3H), 2.15-1.97 (m, 2H). HPLC (Condition A): Rt 3.34 min (purity 97.1%). MS (ESI+): 375.5.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13]CC)=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([C:16]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[C:3]=1[Cl:29].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([C:16]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[C:3]=1[Cl:29]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3-c3ccccn3)c(Cl)c(Cl)c2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2)c1ccnn1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
1.5 g of ethyl 4,5-dichloro-6-(1-(2-pyridyl)-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxy l ate are dissolved in a mixture of 18 ml of tetrahydrofuran and 2 ml of water. 177 mg of lithium hydroxide monohydrate are added to the solution and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water and 1N hydrochloric acid are added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 1.35 g of 4,5-dichloro-6-(1-(2-pyridyl)-5-pyrazolylcarbonyl)-1,3-benzodioxol e-2-carboxylic acid. Yield: 96%
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH:9]([CH2:20][OH:21])[CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH:9]([CH2:20][O:21][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(CO)CCn1ccc(=O)[nH]c1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(CCn1ccc(=O)[nH]c1=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 81.3 %

Procedure:
A glass tube for microwave was charged with compound 41 (50 mg; 0.155 mmol), trityl chloride (54 mg; 0.19 mmol) and dry pyridine (2 ml). The tube was sealed with a septum cap. The vial was irradiated with MW to reach the temperature of 160° C. for 5 minutes. The irradiating cycle was repeated 3 times, and then the mixture was poured into a round bottom flask. The solvent was removed under reduced pressure and the crude was purified by chromatography using Hexane/EtOAc 40:60 as eluent which gave the title product as a white foam (70 mg, 79%). Rf: 0.27 in Hexane/EtOAc 40:60, M.p: 86-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].[C:15]([N:23]=[C:24]=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.CCOC(C)=O>[C:4]([C:3]1[C:6]([O:10][CH:11]2[CH2:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:24]([NH:23][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1c(N)cccc1OC1CCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(NC(=O)NC(=O)c2ccccc2)cccc1OC1CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To a solution of 2-amino-6-cyclobutoxybenzonitrile (example 162b) (30 mg, 0.16 mmol) in 1,4-dioxane (2 mL) was added benzoyl isocyanate (23 mg, 0.16 mmol). The reaction was stirred at rt under N2 for 19 hours. Upon completion, the reaction was diluted with EtOAc, washed with saturated NaHCO3 (2×), water, brine, dried over MgSO4, filtered and concentrated to provide N-(2-cyano-3-cyclobutoxyphenylcarbamoyl)benzamide (38 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 1.64 (m, 1H), 1.81 (m, 2H), 2.05 (m, 1H), 2.42 (m, 2H), 4.71 (pent, J=7.1 Hz, 1H), 6.05 (d, J=8.2 Hz, 1H), 6.33 (d, J=8.3 Hz, 1H), 7.15 (t, J=8.5 Hz, 1H), 7.45 (m, 1H), 7.56 (m, 2H), 7.87 (m, 1H), 8.05 (m, 1H), 11.35 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[CH:3]=1.II.FC(F)(F)C(O[I:19](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>ClCCl.CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH3:11])[N:5]=[C:6]([CH2:8][CH3:9])[C:7]=1[I:19]
Reactant: CCc1cc(N)cc(CC)n1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(N)c(I)c(CC)n1
Reaction time: 16 h
Yield: 40.2 %

Procedure:
4-amino-2,6-diethylpyridine (D) (1.8 g) was added to a solution of iodine (3.1 g) and [bis(trifluoroacetoxy)iodo]benzene (5.7 g) in a mixture of dichloromethane (70 ml) and methanol (20 ml) and the mixture was stirred for 16 hours. Solvent was removed by evaporation and the residue was partitioned between ethyl acetate and a mixture of saturated sodium metabisulphite solution (50 ml) and saturated sodium carbonate solution (150 ml). The organic phase was separated, washed with saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation with the residue was purified by flash chromatography eluting with dichloromethane/methanol (97:3 v/v) to give 4-amino-2,6-diethyl-3-iodopyridine (E) (1.33 g) as a solid, m.p. 72°-74° C.; NMR (CDCl3): 1.25(m,6H), 2.65(q,2H), 2.96(q,2H), 4.59(broad s,2H), 6.30(s,1H); mass spectrum (chemical ionisation, ammonia): 277(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([N:17]3[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]3)[CH2:7][C:6]2=1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([N:17]3[CH:21]=[C:20]([NH:22][C:34]([C:31]4[CH:32]=[CH:33][C:27]5[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=5[CH:30]=4)=[O:35])[CH:19]=[N:18]3)[CH2:7][C:6]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1)CC(n1cc(N)cn1)CO3
Product: COc1ccc2ncc3c(c2c1)CC(n1cc(NC(=O)c2ccc4c(c2)NC(=O)CS4)cn1)CO3

Procedure:
The titled compound is prepared as a white solid (95 mg, 58% yield) following Scheme 3 and in analogy to Example 1 using 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-1H-pyrazol-4-ylamine (100 mg, 0.34 mmol, 1.0 eq) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (85 mg, 0.40 mmol, 1.2 eq) as starting materials.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11](Cl)=[O:12].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([C:11]([C:25]2[S:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[CH:27][CH:26]=2)=[O:12])[CH:14]=1
Reactant: Fc1ccc(-c2cccs2)cc1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc(F)cc2)s1)c1cc(Br)ccc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
AlCl3 (1.5 g, 11 mmol) was dissolved in 10 mL methylene chloride and cooled to −10° C., followed by addition of 5-bromo-2-chloro-benzoyl chloride 2a (2.54 g, 10 mmol) and 2-(4-fluorophenyl)thiophene 9b (1.78 g, 10 mmol). The reaction mixture was stirred for 30 minutes and then warmed to room temperature and stirred for another 16 hours. Thereafter, the reaction mixture was cooled to −10° C. The reaction mixture was extracted with ethyl acetate (50 mL×2) after a small amount of water and 20 mL 1 M hydrochloric acid were added. The organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone 9c (1.5 g, yellow solid), yield: 37.9%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](Cl)=[O:23])=[CH:14]1>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:22]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:14]=1)=[O:23]
Reactant: OCC1CCN2CCCCC2C1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12

Procedure:
The title compound was prepared from ax-2-hydroxymethylquinolizidine (D4) and indole-3-carboxylic acid chloride using the method of Example 1. The product was purified by chromatography on neutral alumina eluting with ethyl acetate, followed by crystallisation from ether/pentane, to give the title compound (E9a) as a white solid mp 156°-157° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:42])([F:41])[CH2:16][N:17]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1>>[F:40][C:37]([F:38])([F:39])[CH2:36][N:17]([CH2:16][C:15]([F:14])([F:41])[F:42])[C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:32][CH:33]=3)=[N:24][C:20]=2[CH:19]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1ccc(-c2nc3cc(N(CC(F)(F)F)CC(F)(F)F)ccc3[nH]2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(N(CC(F)(F)F)CC(F)(F)F)ccc3[nH]2)cc1

Procedure:
Compound 456 was prepared from 4-morpholinoaniline and 4-(5-bis(2,2,2-trifluoroethyl)amino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C28H25F6N5O2: 578.19; found: 578.04.
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:13]([NH2:16])=[N:12][NH:11][C:10]=2[C:9]1([CH3:18])[CH3:17])=O)(C)(C)C.[Cl:19][CH:20]([C:24](=O)[CH3:25])[C:21](=O)[CH3:22].Cl>CC(O)=O>[ClH:19].[Cl:19][C:20]1[C:24]([CH3:25])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[C:9]([CH3:17])([CH3:18])[NH:8][CH2:15][C:14]3=2)[C:21]=1[CH3:22]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)NC3
Reaction time: 4 h
Yield: 136.5 %

Procedure:
A mixture of 3-amino-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (500 mg; 1.98 mmol; 1 eq.) and 3-chloro-pentane-2,4-dione (226 μL; 1.98 mmol; 1.00 eq.) in AcOH (1.5 mL) was stirred at room temperature for 1 hour whereupon 32% aq. HCl (584 μL; 5.94 mmol; 3 eq.) was added. The resulting mixture was stirred for 4 hours then poured onto iPrOH (6 mL). The formed precipitate was filtered off and dried to afford the title compound (388 mg, 68%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.37 (brs, 2H), 4.59 (s, 2H), 2.83 (s, 3H), 2.62 (s, 3H), 1.74 (s, 6H). HPLC (max plot) 98.1%, Rt 1.97 min. UPLC/MS: (MS+) 234.1 ([M+H]+).