Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[CH2:35][O:34][C@H:33]5[C@@H:28]([O:29][CH:30]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:31][CH2:32]5)[CH2:27]4)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:42])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC1(C)C(C)(C)OB([C:80]2[CH:89]=[CH:88][C:83]([C:84]([O:86][CH3:87])=[O:85])=[CH:82][CH:81]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:42][C:9]1[CH:10]=[C:11]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C:15]([O:25][C@H:26]3[CH2:35][O:34][C@H:33]4[C@@H:28]([O:29][CH:30]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[O:31][CH2:32]4)[CH2:27]3)=[N:14][C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:80]2[CH:89]=[CH:88][C:83]([C:84]([O:86][CH3:87])=[O:85])=[CH:82][CH:81]=2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@@H]6COC(c7ccccc7)O[C@H]6C5)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-(4-bromophenyl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (586 mg, 0.871 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (36 mg, 0.088 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (297 mg, 1.132 mmol), and tribasic potassium phosphate (554 mg, 2.61 mmol) in tolune (2 mL) and water (0.1 mL) under nitrogen was added palladium acetate (10 mg, 0.045 mmol). The mixture was stirred at 100° C. for 16 hours, then allowed to cool to room temperature. The mixture was filtered, concentrated under reduced pressure, and chromatographed using a Biotage™ 50 g silica gel cartridge eluted with 0-30% EtOAc in 1:1 Hexane/DCM over 30 column volumes. The product fractions were concentrated under reduced pressure to provide the desired product as a foamy off-white solid. LC-MS: calculated for C39H42ClN3O7Si 727.25, observed m/e: 728.33 (M+H)+ (Rt 3.11/4 min).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:9][C:10](=[O:25])[N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[CH2:12]1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:7][CH:8]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:9][C:10]([N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[CH2:12]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2ccnc2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CC(=O)N1Cc2ccccc2-n2ccnc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of [3-oxo-3-(4H,6H-3,5,10b-triaza-benzo[e]azulen-5-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (3 mL), was added trifluoroacetic acid (0.18 nit, 3 mL/mmol)). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 3-amino-1-(4H,6H-3,5,10b-triaza-benzo[e]azulen-5-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one (30 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].Cl[CH2:14][C:15]1[C:16]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC#N>[CH:24]([NH:23][C:16]1[C:15]([CH2:14][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[C:5]#[N:6])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[N:17]=1)([CH3:26])[CH3:25]
Reactant: CSc1ncc(CCl)c(NC(C)C)n1
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1ncc(CNc2cc(C#N)cc([N+](=O)[O-])c2)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of 3-amino-5-nitrobenzonitrile (3.59 g, 22 mmol) in CH3CN (10 mL) was added dropwise to a mixture of 5-(chloromethyl)-N-isopropyl-2-(methylthio)pyrimidin-4-amine from Example A9 (5 g, 22 mmol), sodium iodide (0.33 g, 2.2 mmol), and diisopropylethylamine (2 mL, 12 mmol) in CH3CN (100 mL) at 0° C. The resultant reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was diluted with water, and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), concentrated and purified by silica gel chromatography to afford 3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile (2.2 g, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1 H), 7.74 (s, 1 H), 7.56 (s, 1 H), 7.32 (s, 1H), 7.08 (m, 1 H), 6.63 (d, J=7.6 Hz, 1 H), 4.30 (m, 1 H), 4.15 (s, 2 H), 2.50 (s, 3 H), 1.17-1.15 (d, J=6.4 Hz, 6 H); MS (ESI) m/z: 359.2[M+H]+.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][N:18]([C:2]([Cl:1])=[O:4])[CH2:17][CH2:16]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
Triphosgene (1.78 g, 6 mmol) was dissolved in benzene (120 ml), followed by the addition of a solution of 4-dimethylaminopiperidine (1.96 g, 15.3 mmol) in benzene and triethylamine (1.82 g, 18 mmol). The resulting mixture was stirred overnight at room temperature. Chloroform was added to the reaction mixture, and the resulting mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was then purified by chromatography on a silica gel (chloroform-acetone mixed solvent [1:2]), whereby 4-dimethylaminopiperidinocarbonyl chloride (465 mg, 16%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C(=O)([O-])O.[Na+]>CN(C=O)C.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.Cl[Pd]Cl>[CH3:19][N:20]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:18])[C:11]4[C:16]([CH:17]=3)=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:4][CH:3]=2)[CH:22]=[N:21]1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2cnccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc(-c3cc4cnccc4c(=O)[nH]3)cc2)cn1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A suspension of 3-(4-bromo-phenyl)-2H-[2,6]naphthyridin-1-one (55.0 mg, 0.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (57 mg, 0.27 mmol) and sodium hydrogen carbonate (18.4 mg, 0.22 mmol) in DMF (0.5 ml) and water (0.25 ml) is flushed with nitrogen and heated to 40° C. Then bis(triphenylphosphine)-palladium(II)-chloride (2.6 mg, 0.004 mmol) is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off washed with water and 2-propanol and dried under vacuum to afford 3-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-2H-[2,6]naphthyridin-1-one as grey solid; HPLC/MS 1.47 min (A), [M+H] 303;
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]([C:22]2[N:26]3[N:27]=[C:28]([C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[CH:29]=[CH:30][C:25]3=[N:24][CH:23]=2)(O)[CH3:20])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7](COCC[Si](C)(C)C)[CH:6]=2.FC1C=C2C(C=NN2COCC[Si](C)(C)C)=CC=1C(C1N2N=C(C3C=NN(C)C=3)C=CC2=NC=1)(O)C.II.O[PH2]=O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:19]([C:22]1[N:26]2[N:27]=[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1)[CH3:20]
Reactant: Cn1cc(-c2ccc3ncc(C(C)(O)c4cc5cn(COCC[Si](C)(C)C)nc5cc4F)n3n2)cn1
Agent: Cn1cc(-c2ccc3ncc(C(C)(O)c4cc5cnn(COCC[Si](C)(C)C)c5cc4F)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CC(c1cc2cn[nH]c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Reaction time: 0.08 h

Procedure:
A mixture of (rac)-1-[6-Fluoro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-1-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-ethanol and (rac)-1-[6-Fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-1-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-ethanol (Stage 164.1, 563 mg, 1.109 mmol), iodine (844 mg, 3.33 mmol), H3PO2 (1.815 mL of a 50% aqueous solution, 16.64 mmol) and acetic acid (9.5 mL) were introduced in a microwave tube and the mixture was subjected to MW-irradiation at 150° C. for 5 min. The solvent was removed and the residue was taken up with 1 N HCl and washed with EtOAc three times. The aqueous layer was basified with NaOH pellets and extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The title compound was obtained as a racemic mixture (tR 1.0 min (conditions 2), MH+=362).
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[K+].[CH3:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]#[N:16])=[N:10]1.S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:12]1[C:11]([C:15]#[N:16])=[N:10][N:9]([CH3:8])[C:13]=1[CH3:14]
Reactant: Cc1cc(C#N)nn1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(Br)c(C#N)nn1C
Reaction time: 0.5 h

Procedure:
A solution of bromine (5.1 g, 32 mmol) in acetic acid (10 mL) was added dropwise to a solution of potassium acetate (3.9 g, 40 mmol) and 1,5-dimethyl-1H-pyrazole-3-carbonitrile in acetic acid (50 mL). Following the addition, the reaction was stirred for 30 minutes. Saturated aqueous sodium hydrogensulfite was added, and the mixture was stirred until it became colorless. The volatiles were removed under reduced pressure, and the residue was stirred with water to form a solid. The solid was isolated by filtration, washed with water, and recrystallized from ethanol and then from hexane to provide 2.5 g of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile as colorless needles, mp 92-94° C. Anal. Calcd. for C6H6BrN3: C, 36.03; H, 3.02; N, 21.01. Found: C, 36.04; H, 2.86; N, 20.99.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH:19]([CH3:21])[CH3:20])[N:11]=2)=[C:4]([F:22])[CH:3]=1.[Cl:23]N1C(=O)CCC1=O>CN(C)C=O>[Cl:23][C:14]1[C:10]([C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=2[F:22])=[N:11][N:12]([CH:19]([CH3:20])[CH3:21])[C:13]=1[C:15]([F:17])([F:18])[F:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(-c2cc(C(F)(F)F)n(C(C)C)n2)c(F)cc1Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(C(C)C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 87.3 %

Procedure:
To a solution of 1.6 g of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-(1-methylethyl)-5-(trifluoromethyl)-1H-pyrazole in 20 mL of dimethylformamide was added 2.0 g of N-chlorosuccinimide. The solution was heated to 80° C. for 2 hours, allowed to cool and poured into ice water. The aqueous mixture was extracted three times with methylene chloride, the combined organic extracts washed with water, dried with MgSO4 and concentrated to give a crude oil. The oil was purified by chromatography and distilled bulb-to-bulb to afford 1.54 g of 4-chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-(1-methylethyl)-5-(trifluoromethyl)-1H-pyrazole as a yellow oil, nD 1.5192 (24° C.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>CN1C(=O)CCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:18][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[N+:11]([O-:13])=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of 4-fluoro-3-nitroacetophenone (165 g, 0.9 mol) in NMP (350 ml) was added 3-bromoaniline (98 ml, 0.9 mol) and triethyl amine (125.4 ml, 0.9 mol) and the reaction mixture was stirred at 80° C. for 6 hours and then left with stirring at room temperature over night. The resultant suspension was poured into ice-water and the precipitate was filtered off and washed with water and diethyl ether, successively. Drying in the air afforded the desired product (262g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=3[CH:20]=2)=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=3[C:20]=2[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)=[O:6])=[CH:15][CH:14]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cccc(C)c2)cc1
Yield: 163.5 %

Procedure:
In a manner similar to that described in Preparation 2, 3.1 g (20 mmol) of 3-methylbenzoylchloride, 2 g (7.4 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and 6.7 g (50 mmol) of AlCl3 were converted to 4.7 g of the title compound, isolated as yellow amorphous powder.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([CH3:15])[CH2:8][CH2:9][O:10]2.Cl.O>CO>[CH3:15][CH:7]1[C:6]2[C:5]([OH:4])=[CH:14][CH:13]=[CH:12][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: COCOc1cccc2c1C(C)CCO2
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1CCOc2cccc(O)c21
Temperature: 50 °C
Yield: 102.9 %

Procedure:
In a 50 mL round-bottomed flask 5-(methoxymethoxy)-4-methyl-chromane (Intermediate 210, 50.3 mg, 0.229 mmol) was dissolved in Methanol (4 mL) to give a pale yellow solution. A 2M aqueous solution of HCl (0.100 mL, 0.200 mmol) was added. The reaction mixture was stirred at 50° C. Sequential addition of 2M/H2O solution of HCl (0.100 mL, 0.200 mmol) were added until completion of reaction. The reaction mixture was quenched with 10 mL of water and diluted with 25 mL of DCM. Phases were separated through a phase separator cartridge. The organic layer was evaporated in vacuo affording the title compound (38.7 mg) as orange oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][N:19]([CH2:24][CH2:25][CH2:26][NH2:27])[CH2:20][CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH2:24][CH2:25][CH2:26][NH:27][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1)[CH2:20][CH2:21][CH2:22][NH:23][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(CCCN)CCCN
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(NCCCN(C)CCCNc2ccc([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To 5-fluoro-2-nitrotoluene (50.0 g, 0.32 mol) was added sodium carbonate (17.1 g, 0.16 mol) at 60° C. 3,3′-Diamino-N-methyldipropylamine (23.7 g, 0.16 mol) was then carefully added dropwise (exothermic reaction). The resulting mixture was heated at 100° C. for 12 hours. 100 ml toluene were added to the cooled reaction mixture causing the inorganic salts to precipitate, which were filtered off. The organic phase was then concentrated down under vacuum in a rotovap to afford the product as a residue in the form of a yellow orange oil. Yield: 52.5 g (78.4%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.71 (m, 4H); 2.18 (s, 3H); 2.40 (m, 4H); 2.55 (s, 6H); 3.17 (m, 4H); 6.45 (s, 2H); 6.48 (d, 2H); 7.08 (br., 2×NH); 7.92 (d, 2H).
Reaction SMILES: [Si]([C:5]([F:8])([F:7])[F:6])(C)(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:23][CH2:22][C@:21]2([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:17]1[CH2:18][C:19]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:20]=12)=[O:15])([CH3:12])([CH3:11])[CH3:10].[F-].[Cs+].Cl.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:23][CH2:22][C@:21]2([CH3:27])[C:24]([CH3:25])([CH3:26])[C@H:17]1[CH2:18][C:19]1[CH:31]=[CH:30][C:29]([C:32]([OH:34])([CH3:33])[C:5]([F:8])([F:7])[F:6])=[CH:28][C:20]=12)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(=O)c1ccc2c(c1)[C@]1(C)CCN(C(=O)OC(C)(C)C)[C@H](C2)C1(C)C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@]2(C)c3cc(C(C)(O)C(F)(F)F)ccc3C[C@@H]1C2(C)C
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
Me3SiCF3 (2 M in tetrahydrofuran, 0.42 mL) is added dropwise to a mixture of (2R,6S)-8-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.30 g) and CsF (13 mg) in tetrahydrofuran (3 mL) cooled to ca. −5° C. The mixture is stirred at −5° C. for 1.5 h. Then, 1 M aqueous HCl solution (70 mL) is added and the mixture is stirred for 1 h. The mixture is basified using aqueous K2CO3 solution and then extracted with ethyl acetate. The combined organic extracts are washed with brine and dried (MgSO4). The solvent is evaporated to give the crude title compound that is submitted for cleaving the protective group without further purification.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:23]1([C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:3]2[N:2]=[N:1][C:5]([C:6]3[CH:7]=[C:8]([CH:12]=[CH:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=3)=[N:4]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCC=Cc1cccc(-c2nnn[nH]2)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC=Cc1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[3-(1H-tetrazol-5-yl)phenyl]-2-propenol (2.02 g) in dry dichloromethane (50 ml) was added triethylamine (1.5 ml) followed by triphenylchloromethane (2.8 g) in dry dichlormethane. The solution was stirred at room temperature for 90 minutes, washed with water (50 ml), followed by sodium bicarbonate solution (5%; 50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale brown viscous oil which crystallised on standing to a cream solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[C:27](B3OCC(C)(C)CO3)[CH:26]=[CH:25][C:24]=2[F:37])[C:18]=1[C:38]#[N:39]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[C:27]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]4=[N:4][CH:3]=3)[CH:26]=[CH:25][C:24]=2[F:37])[C:18]=1[C:38]#[N:39]
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(F)c3C#N)c2)OC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(F)c4C#N)c3)cnc2c1F
Yield: 75 %

Procedure:
3-Bromo-8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridine (0.10 g, 0.36 mmol) and 3,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (0.16 g, 0.47 mmol) were coupled following the procedure in Example 1 to afford 3,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as a white amorphous solid (110 mg, 74%): δH (360 MHz, CDCl3) 1.73 (6H, s), 2.10 (1H, s), 7.21 (1H, dd, J 7 and 7), 7.30 (1H, dd, J 8 and 8), 7.38-7.44 (2H, m), 7.61-7.72 (4H, m), 8.23 (1H, d, J 7); m/z (ES+) 408 (M++H).
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.[F-].[Cs+]>O1CCOCC1>[CH:10]1([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1cccnc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: O=Cc1cccnc1C1CC1
Temperature: 100 °C

Procedure:
A 40 mL reaction vial is charged with 3 mL of 1,4-dioxane and a stirbar. Degas with nitrogen for 5 minutes. Next, the vial is charged with 2-bromonicotinaldehyde (645.134 μmoles, 120.000 mg), cyclopropylboronic acid (1.290 mmoles, 110.831 mg), and cesium fluoride (1.935 mmoles, 293.995 mg). The vial is then degassed again with nitrogen. Next, (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (32.257 μmoles, 26.342 mg) is added and the reaction mixture is heated to 100° C. under nitrogen. Upon reaction completion, the mixture is cooled to room temperature, filtered over a pad of diatomaceous earth with ethyl acetate afford the title compound. GCMS (m/z): 146 (M).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:23]=2)=[CH:4][N:3]=[CH:2]1.Cl>CO.O1CCOCC1>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:23]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cncs3)cc2C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ncc(-c2ccc3c(c2)CNCCO3)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl 7-(thiazol-5-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (41 mg, 0.12 mmol) in methanol (5.0 mL) added 4.0 M hydrogen chloride in dioxane (3.0 mL) and the mixture stirred at 25° C. for 20 minutes then concentrated to give 7-(thiazol-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.CCOC(C)=O>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a suspension of 4-amino-benzamide (1.00 g, 7.34 mmol) in 50 mL of 1:4 CH3CN/DCM at 0° C. was added N-bromosuccinimide (NBS) (1.31 g, 7.34 mmol) in 20 mL of 1:1 CH3CN/DCM. The mixture was warmed to RT and stirred for 16 h under Ar. Treated with 100 mL of EtOAc, the mixture was washed with H2O (2×30 mL), brine (20 mL) and dried (Na2SO4). The organic solvent was evaporated in vacuo and the residue was triturated with DCM to give 1.45 g (92%) of the title compound as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C7H7BrN2O, 215.0 (M+H), found 215.1.