Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccnc1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Product: COc1cccc(CNc2cccn3nc(Nc4cccnc4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) and 3-aminopyridine (36.47 mg, 0.3875 mmol) in a manner analogous to Example 2d. Product isolated as an off-white foam (6.22 mg, 5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.65 (s, 1H), 8.89 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 8.08 (m, 1H), 7.97 (d, J=6.4 Hz, 1H), 7.32-7.20 (m, 2H), 6.97 (s, 2H), 6.82-6.72 (m, 2H), 6.62 (m, 1H), 6.32 (d, J=8.1 Hz, 1H), 4.50 (d, J=6.1 Hz, 2H), 3.72 (s, 3H). MS=347 (MH)+.
Reaction SMILES: [C:1]([C:5]1[NH:23][C:8]2=[C:9]3[C:14](=[C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]4=[C:7]2[N:6]=1)[C:13](=[O:22])[NH:12][CH:11]=[CH:10]3)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27]>CN(C=O)C>[C:1]([C:5]1[NH:23][C:8]2=[C:9]3[C:14](=[C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]4=[C:7]2[N:6]=1)[C:13](=[O:22])[N:12]([CH3:27])[CH:11]=[CH:10]3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1nc2c3ccc(F)cc3c3c(=O)[nH]ccc3c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c3[nH]c(C(C)(C)C)nc3c3ccc(F)cc3c2c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one (40 mg, 0.129 mmol) in dry DMF (1.5 mL) at 0° C. was added NaH (60 wt. %) (6 mg, 0.15 mmol). After stirring for 5 minutes, iodomethane (9 μL, 0.142 mmol) was added, and the reaction mixture was slowly warmed to room temperature over 2 h. The mixture was cooled in ice bath and the reaction was quenched with water. The reaction mixture was diluted with EtOAc, washed with water followed by brine, then dried over Na2SO4. After removal of the solvent the crude was purified by preparative thin layer chromatography (1:9 MeOH:CH2Cl2 as eluent) to obtain the title compound as a mixture of imidazole tautomers.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)#[N:21]>>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([O:19][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Product: CC(C)c1cc(OCc2ccc(C#N)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and 4-cyanobenzyl bromide according to Method A; LC retention time 3.71 min; MS: m/z (ESI) 375 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH2:11][CH:10]([CH2:30][N:31]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([N:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:24])[C:18]=3[C:17]3=[N:25][O:26][C:27]([CH3:28])=[C:16]3[C:15]2=[O:29])[CH2:11][CH:10]([CH2:30][NH2:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1onc2c1c(=O)n(C1CC(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1onc2c1c(=O)n(C1CC(CN)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Yield: 66 %

Procedure:
Hydrogenate 3-azidomethyl-5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.4 mmol) in THF (7.5 mL) and EtOH (50 mL) with 5% Pd/C (0.132 g, at 50 psi and room temperature for 24 H. Filter through celite and concentrate to dryness. Dissolve in CHCl3. Wash 2× with sat. aq NaHCO3, wash with brine, dry over Na2SO4, filter and concentrate to dryness to afford the title compound (413 mg, 66%) as a tan foam as a mixture of cis isomers. MS(IS) 447.1 (M+); TLC (10% MeOH/CHCl3) Rf=0.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][CH:14]([NH2:19])[C:15]([F:18])([F:17])[F:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:19][CH:14]([CH3:13])[C:15]([F:18])([F:17])[F:16]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(N)C(F)(F)F
Product: COc1ccc(CNC(C)C(F)(F)F)cc1OC

Procedure:
The secondary amines can easily be prepared according to known methods by reaction of an appropriately substituted aromatic aldehyde with a primary amine and hydrogenation of the addition product. By condensing 3,4-dimethoxybenzaldehyde with 1-methyl-2,2,2-trifluoroethylamine and hydrogenation of the condensate, N-(3,4-dimethoxybenzyl)-N-(1-methyl-2,2,2-trifluoroethyl)-amine is obtained according to the following reaction scheme: ##STR10##
Reaction SMILES: Cl[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Se-2:13].[Na+].[Na+].Cl>C(O)C>[SeH:13][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [Se-2]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C([SeH])C(=O)OCC

Procedure:
15 mmol of ClCH(COOC2H5)2 and 10 mmol of sodium selenide were heated in 50 ml of ethanol under reflux for 2 hours. After completion of the reaction, the reaction solution was slightly acidified with 1N HCl. Then, after insoluble material was removed from the solution, the reaction solvent was distilled off to obtain HSeCH(COOC2H5)2. The thus obtained HSeCH(COOC2H5)2 was put in aqueous ammonia and the reaction was allowed to proceed at 50° C. for 6 hours. After completion of the reaction, the solvent was distilled off to obtain HSeCH(CONH2)2. To the thus obtained HSeCH(CONH2)2 were added 50 ml of tetrahydrofuran and then 2 mmol of lithium aluminum hydride. The resulting mixture was heated under reflux for 10 hours to reduce the amide. After completion of the reaction, the insoluble portion was removed and the solvent was distilled off under reduced pressure. Then, the residue was purified by using cation exchange resin to obtain 2 mmol of 2-seleno-1,3-diaminopropane HSeCH(CH2NH2)2. To the thus obtained HSeCH(CH2NH2)2 was added 20 ml of an aqueous solution containing 2 mmol of potassium tetrachloroplatinate (II) and the resulting mixture was allowed to stand at room temperature for 4 days, so that a precipitate was formed. The precipitate was separated by filtration and dried to obtain 1.1 mmol of HSeCH(CH2NH2)2PtCl2.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]([CH3:16])([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]>CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2([O:2][CH3:1])[C:5]([CH3:16])([CH3:15])[O:7]2)=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: CC(C)(Cl)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(Cl)cc2)OC1(C)C

Procedure:
57.0 g (1.056 mols) of sodium methylate are dissolved in 360 ml of methanol, and 208.4 g (0.96 mol) of 2-chloro-1-(4-chlorophenyl)-2-methylpropan-1-one are added dropwise to this solution at reflux temperature. The methanol is then removed by distillation. The residue is poured into ice water and the mixture is extracted with diethyl ether. The ether solution is washed with water, dried over Na2SO4 and concentrated. The resulting oil is purified by vacuum distillation.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:41][CH3:42])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[C:31]4[N:30]=[CH:29][N:28]=[CH:27][C:26]=4[NH:25][N:24]=3)=[O:22])=[CH:18][N:17]([CH:32]([CH3:40])[C:33]([O:35]C(C)(C)C)=[O:34])[N:16]=2)[CH:14]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:41][CH3:42])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[C:31]4[N:30]=[CH:29][N:28]=[CH:27][C:26]=4[NH:25][N:24]=3)=[O:22])=[CH:18][N:17]([CH:32]([CH3:40])[C:33]([OH:35])=[O:34])[N:16]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)OC(C)(C)C)cc1NC(=O)c1n[nH]c2cncnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (10 mL) was added dropwise to a solution of tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)propanoate (0.945 g, 1.90 mmol, 1 equiv) in dichloromethane (10 mL). After 2 h, the reaction mixture was concentrated in vacuo to afford crude product (quantitative) which was used without further purification. LCMS (ESI): M+H=441.1.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>>[C:23](=[O:24])([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])[O:25][CH2:26][CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CC(O)CC(=O)C1C(C)C=CCC1(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)OC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 3-hydroxy-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (8.0 mmol) in pyridine (1.85 g, 23.4 mmol) was treated at 0° C. with ethyl chloroformate (1.24 g, 23.4 mmol). The reaction solution was stirred at room temperature for 36 hours, treated with 5% aqueous HCl and extracted twice with ether, washed (H2O, saturated aqueous NaHCO3, then brine), dried over Na2SO4 and concentrated. The oil (2.38 g) was purified by flash-chromatography (cyclohexane/AcOEt=98:2), using SiO2 (100 g). Yield: 2.06 g (78%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH2:24])=[CH:19][C:20]=3[NH:21]2)=[CH:13][CH:12]=1.[CH2:25]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH:24][CH3:25])=[CH:19][C:20]=3[NH:21]2)=[CH:13][CH:12]=1
Reactant: Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-amine (95 mg, 0.28 mmol), paraformaldehyde (43 mg, 1.43 mmol), and NaOMe (492 mg, 25% MeOH solution, 2.3 mmol) in 8 mL of MeOH was heated at reflux for 1.5 h under Ar atmosphere and cooled to rt. To this mixture was added NaBH4 (54 mg, 1.43 mmol) and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was quenched onto ice. It was extracted with ether (3×30 mL) and the combined organic phase was dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-carbazol-2-amine (AD-CB-003P-WZ0141) as a light-brown solid (55 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.77 (t, J=8.8 Hz, 2H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 6.77 (s, 1H), 6.53 (dd, J=8.4, 2.0 Hz, 1H), 6.46 (s, 1H), 4.62 9 m, 1H), 4.50 (m, 1H), 4.13 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H), 3.83 (s, 1H), 3.79-3.67 (m, 6H), 2.87 (s, 3H); MS (ESI) m/z 347 (M+H+).
Reaction SMILES: [C:1]([C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[C:1]([C:9]1[N+:14]([O-:24])=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=O)c2ccccc2)[n+]1[O-]
Reaction time: 8 h

Procedure:
The 6-benzoyl-2-methylpyridine (3.9 g, 21 mmol), in 20 ml CHCl3, is added over 1 hour to 4.2 g (21 mmol) m-chloroperbenzoic acid (in 50 ml CHCl3). The temperature is kept below 25° as the mixture is stirred overnight. The reaction is diluted with CHCl3, washed with sat. NaHSO3, water, 20% NaHCO3 (2×) and then water, dried, stripped and finally titrated with hexane/ethyl acetate to give 6-benzoyl-2-methylpyridine N-oxide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:4][C:5](=O)[NH:6][C:7]=1[CH2:8][CH2:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[N:6]=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]([CH3:1])=[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1[nH]c(=O)nc(-c2cccc(C(F)(F)F)c2)c1C
Product: CCCc1nc(Cl)nc(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
A mixture of 5-methyl-6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one (64 mg) and phosphorus oxychloride (3 mL) was stirred and heated at reflux for 24 h, then allowed to cool and poured onto a mixture of ice/ether (20 mL). The ether layer was separated, washed with saturated sodium carbonate solution (10 mL) and water (10 mL), dried over sodium sulphate, and evaporated at reduced pressure to afford 2-chloro-5-methyl-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine as an oil (64 mg).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][NH2:33].C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[N:33]=[CH:3][CH:4]=2)=[N:8]1
Reactant: NNCC(F)(F)F
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2CC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of 2,2,2-trifluoroethylhydrazine (0.0483 mL) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[C:2]([F:43])[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cn[nH]c3)sc2n1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(F)c(-c3cn[nH]c3)sc2n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 4.8 %

Procedure:
A stirred solution of N-[3-bromo-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridin-4-yl]-3-chlorobenzenesulfonamide (Example 100) (120 mg, 0.248 mmol) in THF (1.5 mL) was cooled to −78° C. using a dry ice/acetone bath. n-BuLi (2.5M in Hexane) (0.109 mL, 0.273 mmol) was added dropwise and the mixture stirred at −78° C. for ca. 1.5 h. Then, N-fluorobenzenesulfonimide (82 mg, 0.260 mmol), pre-dissolved in THF (0.5 mL), was added dropwise and the mixture stirred at −78° C. for ca. 1 h and then left to stir at RT for 3 days (ca. 89 h). The reaction mixture was then quenched with saturated NH4Cl solution (ca. 20 mL), extracted with ethyl acetate (20 mL×3) and the combined organics dried and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in DCM and further purified by MDAP (acidic conditions), to give the title compound (5 mg). LCMS (A) m/z: 423 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].CCN(CC)CC.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH:24][C:35]([NH:34][CH2:32][CH3:33])=[O:36]
Reactant: CCN=C=O
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:23]#[C:22][C:21]([O:20][CH3:19])([CH3:25])[CH3:24])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CC(C)(C)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2

Procedure:
3.57 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 4 hours with 1.22 g (12.5 mmol) of 3-methoxy-3-methyl-1-butyne, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 149°-150°.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Mg].II.[C:16](=[O:18])=[O:17].Cl>C1COCC1.O>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Br)c2ccccc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,4-dibromonaphthalene (100 g) in THF (500 ml) is added to magnesium (8.49 g) and iodine (trace) in THF (200 ml) over about 2 h and heated at 65-75° C. for up to 7 h (typically 3-4 h) to prepare a solution of the Grignard reagent. The solution is cooled to 0-10° C. and carbon dioxide gas is passed through the solution for 10-16 h. Water (100 ml) is added slowly, and after stirring for about 30 min at 0-10° C., is acidified (typically to pH 2-3) with hydrochloric acid. The THF layer is separated off, and concentrated. The residue is added to aqueous sodium carbonate (20%, 500 ml) and washed with toluene (2×200 ml). The aqueous solution is treated with hydrochloric acid (typically to pH 2-3). The product is filtered off, washed with water, and dried under vacuum at about 90-100° C. for about 12 h (dry weight 60 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>C1COCC1>[CH2:38]([N:40]([CH2:41][CH3:42])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:33]2[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.385 g, 0.717 mmol) and diethylamine (2.0 mL, 19 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 20 minutes to give diethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine a clear amber gum (0.269 g, 85.7%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a brown foam (0.253 g); Mass Spectrum (+EI, [M+H]+) m/z 438. 1HNMR (500 MHz, DMSO-d6): δ10.11-10.12 (br, 1H), 8.74 (d, 1H, J=8.66 Hz), 8.50-8.52 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.37 (d, 1H, J=2.20 Hz), 7.21 (dd, 1H, J=9.27 Hz and 2.32 Hz), 4.41-4.43 (m, 2H), 4.05 (s, 3H), 3.49-3.52 (m, 2H), 3.15-3.25 (m, 4H), 1.22-1.25 ppm (m, 6H).
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[OH:3].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinic acid and ethyl bromoacetate are reacted together to give ethoxycarbonylmethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-4-(trifluoromethyl)benzoic acid (CAS RN 115754-20-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (37%). MS (ESI): m/z=405.10 [M+H]+.