Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]=[O:14])=[CH:5][NH:6]2.[CH3:15][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]([OH:14])[CH3:15])=[CH:5][NH:6]2
Reactant: O=CCc1c[nH]c2c(F)ccc(Br)c12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)Cc1c[nH]c2c(F)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of (4-bromo-7-fluoro-1H-indol-3-yl)-acetaldehyde (358 mg, 1.40 mmol) in THF (10 mL) was added a solution of MeMgBr (4.0 mL of 1.4 M in toluene-THF (75:25), 5.59 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 30% EtOAc in hexanes) to give 158 mg (42%) of the title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.97 (bs, 1H), 7.11 (dd, J=8.10, 4.20 Hz, 1H), 6.70 (dd, J=10.2, 8.10 Hz, 1H), 4.18 (m, 1H), 3.29(dd, J=14.5, 3.93 Hz, 1H), 2.87 (dd, J=14.5, 8.43 Hz, 1H), 2.16 (bs, 1H), 1.29 (d, J=6.18 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([Cl:21])=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: OC(=S)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: S=C(Cl)Cc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 17.5 g (0.0595 mol) of p-(p-chlorophenoxy)-phenylthio-acetic acid (Code No. CRL 40,271) and of 21.6 ml (0.3000 mol) of thionyl chloride is heated under reflux for 30 minutes. After having taken up the reaction mixture in benzene, filtered the solution in the presence of charcoal and evaporated the solvent, 18.5 g of a limpid orange-yellow oil are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.[C-:16]#[N:17].[Na+]>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:16]#[N:17]
Reactant: FC(F)(F)COc1c(Cl)cccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(Cl)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-3-chlorobenzyl bromide (1.6 g, 5.4 mmol) from Step 2 above in DMF (12 mL) was added NaCN (0.28 g, 5.7 mmol). The solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-20% EtOAc:hexanes to give 2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetonitrile as a colorless oil.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:20])[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:21]S(C)=O>[H-].[Na+]>[CH3:1][O:2][N:3]([CH3:20])[C:4]([C@@H:5]1[CH2:21][C@H:6]1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: CS(C)=O
Reactant: COc1ccc2cccc(C=CC(=O)N(C)OC)c2c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cccc([C@@H]3C[C@H]3C(=O)N(C)OC)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
5.8 g (21.4 mmol) of the compound obtained in Step F dissolved in 30 ml of DMSO are added to a suspension of ylid produced starting from 10.6 g (2 eq) of Me3SOI dissolved while hot in 50 ml of DMSO and 1.25 g of NaH. After 15 hours' stirring at room temperature and 4 hours at 50° C., the title cyclopropane amide is obtained in the form of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[N+:13]=[N-:14]
Reactant: Nc1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
5-Amino-2-chloropyridine (2.28 g; 17.7 mmol; 1.0 eq.) was dissolved in TFA (7 mL). Sodium nitrite (1.35 g; 19.5 mmol; 1.1 eq.) was then added portion wise to this solution maintained at 0° C. Reaction mixture was stirred at 0° C. for 30 min before the addition of and ice-cold solution of sodium azide (1.15 g; 17.7 mmol; 1.0 eq.) in water (8 mL). It was stirred at 0° C. for 1 h. TFA was then removed and the residue was dissolved in EtOAc. Organic phase was washed with an aqueous saturated solution of NaHCO3, brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was purified by flash chromatography on silica (heptane:EtOAc, gradient from 95:5 to 80:20) to afford the title compound as a brown oil (1.89 g, 69%). 1H NMR (300 Mz, DMSO-d6) δ 8.23 (dd, J=0.6, 2.9 Hz, 1H), 7.68 (dd, J=2.9, 8.6 Hz, 1H), 7.54 (dd, J=0.6, 8.6 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[Cl:33][C:34]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:35]=1[O:36][CH2:37][C:38]([OH:40])=O.[Cl:49][C:50]1[CH:51]=[C:52]([NH:64][CH3:65])[CH:53]=[CH:54][C:55]=1[O:56][CH2:57][CH2:58][N:59]([CH2:62][CH3:63])[CH2:60][CH3:61].C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:49][C:50]1[CH:51]=[C:52]([N:64]([CH3:65])[C:38](=[O:40])[CH2:37][O:36][C:35]2[CH:41]=[CH:42][C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:34]=2[Cl:33])[CH:53]=[CH:54][C:55]=1[O:56][CH2:57][CH2:58][N:59]([CH2:62][CH3:63])[CH2:60][CH3:61]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(NC)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCOc1ccc(N(C)C(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
293 mg (0.911 mmol) of TBTU and 123 mg (0.911 mmol) of HOBT were added to a suspension of 231 mg (0.911 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product Z2b) in 5 mL abs. THF and the mixture was stirred for 10 minutes at RT. 180 mg (0.701 mmol) of [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-methyl-amine and 0.18 mL (1.051 mmol) of ethyl-diisopropylamine were added, the mixture was stirred for 16 hours at RT and evaporated down i. vac. The residue was purified by column chromatography (silica gel, silica gel, dichloromethane/MeOH/conc. aqueous ammonia 85:15:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH2:35])[CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: NCCOCCCc1cccnc1
Reactant: O=[N+]([O-])c1c(Cl)nc2c(c1Cl)CCCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Temperature: 55 °C
Yield: 94.7 %

Procedure:
A 200 ml round bottom flask was charged with 2,4-dichloro-3-nitro-5,6,7,8-tetrahydroquinoline (10 g, 0.04 mol), triethylamine (6.1 g, 0.06 mol, 1.5 equivalents) and anhydrous N,N-dimethylformamide (100 mL). To this solution was added 2-(3-pyridin-3-ylpropoxy)ethanamine (7.3 g, 0.04 mol). The reaction mixture was heated to 55° C. and maintained overnight with stirring. The reaction was quenched by pouring into water (1000 mL). The reaction mixture was then extracted with a 1:1 solution of hexane/ethyl acetate (4×200 mL). The organics were combined, washed with brine (300 mL) and concentrated to provide 2-chloro-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as an orange syrup (14.8 g, 94%). TLC (10% MeOH/CH2CL2, Rf=0.84).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH2:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14](C)(C)C([O-])([O-])[O-]>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[O:10][C:13]([CH3:14])=[N:12][N:11]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: NNC(=O)Cc1cccc(Br)c1
Solvent: CC(=O)O
Product: Cc1nnc(Cc2cccc(Br)c2)o1
Temperature: 115 °C
Yield: 53.3 %

Procedure:
To a solution of 2-(3-bromophenyl)acetohydrazide 1104 (1.0 g, 4.37 mmol) in AcOH (10 mL) was added trimethylorthoacetate (2.62 g, 21.83 mmol) and the mixture heated to 115° C. for 18 hours. The volatiles were removed under reduced pressure and the residue purified by reverse phase chromatography to give 0.59 g of 2-(3-bromobenzyl)-5-methyl-1,3,4-oxadiazole 1105. 1H NMR 300 MHz CDCl3: δ 7.45 (m, 2H), 7.23 (m, 2H), 4.12 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)c1
Temperature: 25 °C

Procedure:
500 mg (1.1 mmol) of 2-[4-(3-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester was dissolved in 30 mL of 1:1 mixture of EtOH/EtOAc. To this solution was added SnCl2 (0.87 g, 3.9 mmol). Reaction mixture was heated under reflux for 5 hours. After 5 hours reaction mixture was cooled to room temperature and evaporated. It was redissolved in EtOAc (150 mL) and washed using sat. K2CO3. Organic phase was isolated, washed using brine and water and evaporated to dryness to give Compound 5001. MS: 422.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH2:8]([N:15]([CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH:16]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:17][C:18](O)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]([N:15]([CH:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])[CH:16]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:17][C:18]([NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)CCN
Reactant: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)NCCC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 3,3-dimethyl butylamine (0.6 mL, 4.2 mmol), 3-[benzyl-(1-phenyl-ethyl)-amino]-3-cyclohexyl-propionic acid (1.83 g, 3.8 mmol), HBTU (2.2 g, 5.7 mmol), DIPEA (1.5 mL, 8.6 mmol) and DMF (25 mL) was stirred at room temperature for 14 hours. To the reaction mixture was then added sodium bicarbonate(s) (100 mL) and the desired product was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water, dried over MgSO4 and concentrated to yield a solid. The solid was purified by column chromatography (10% EtOAc/heptane) to yield a residue.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][NH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[F:37])[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:28]=1[CH3:45]>CCOC(C)=O>[F:37][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:36]=1[C:27]([N:12]1[C:11]3[CH:18]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=[CH:9][C:10]=3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1)=[C:28]([CH3:45])[C:29]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])=[N:30]2
Reactant: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl
Reactant: O=S1(=O)CCNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a N2 atmosphere, 6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide (0.0800 g, 0.298 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol). Sodium hydride (0.0143 g, 0.596 mmol) was added and the reaction was allowed to stir at rt for 10 minutes. 4-Chloro-5-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.0950 g, 0.328 mmol) was added and the reaction was heated to 140° C. for 2 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate, then brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase chromatography to afford 4-(5-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide. Mass Spectrum (ESI) m/e=522.2 (M+1)
Reaction SMILES: Cl[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[OH-].[Na+].C(OCC)C>C1C=CC=CC=1>[N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=1[NH:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=1[Br:9]
Reactant: NNC(=O)c1ccccc1Br
Reactant: ClC1=NCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(NNC1=NCCCCC1)c1ccccc1Br
Yield: 38.7 %

Procedure:
To a solution of 7-chloro-3,4,5,6-tetrahydro-2H-azepine (1.32 g, 10 mmol, J. Med. Chem. 30, 1543-49) in benzene (20 ml) was added 2-bromo-benzoic acid hydrazide (1.08 g, 5 mmol) and the mixture was stirred at reflux temperature for 5 hrs. To the cooled reaction mixture was added 10% sodium hydroxide (10 ml) and diethyl ether (20 ml). The mixture was stirred for 30 min., the precipitate filtered off and dried in vacuo at 50° C. for 1 hr. affording 0.6 g of 2-bromo-benzoic acid-N′-(4,5,6,7-tetrahydro-3H-azepin-2-yl)-hydrazide which was dissolved in ethanol (20 ml) followed by addition of TEA (5 ml) and refluxed for 16 hrs. The volatiles were evaporated in vacuo and to the residue was added diethyl ether (10 ml) and ethyl acetate (5 ml). The precipitate was filtered off and dried in vacuo at 50° C. for 1 hr affording 0.35 g (24%) of the title compound as a solid.
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[CH3:34][C:35](C)=[CH:36][Mg]Br>>[CH3:36][C:35](=[CH2:34])[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1)=[O:32]
Reactant: CC(C)=C[Mg]Br
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Product: C=C(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C

Procedure:
To a N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.150 g, 0.340 mmol) at 0° C. was added 2-methylpropenylmagnesium bromide (6.8 mL, 3.4 mmol, 0.5 M solution in THF). The reaction mixture was allowed to stir at room temperature for min. It was quenched with saturated NH4Cl solution (0.5 mL) and was extracted with EtOAc (2×3 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to get a white solid, which was further purified by column chromatography (SiO2, 60-120, product getting eluted in methanol/chloroform:2/98) to give 2-methyl-1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)prop-2-en-1-one (I-83) as a white solid. 1H NMR (DMSO-d6) δ ppm: 1.99 (s, 3H), 5.64 (s, 1H), 6.03 (s, 1H), 6.14 (s, 1H), 6.96-7.02 (m, 4H), 7.10 (t, J=7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.35-7.43 (m, 3H), 7.56 (d, J=8.8 Hz, 2H), 7.88 (d, J=8 Hz, 1H), 7.92 (s, 1H), 8.29 (s, 1H), 9.21 (s, 1H), 9.38 (s, 1H); LCMS: 423 m/e (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:27][CH2:26][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=4)=[CH:3][CH:2]=1.C(O)C.Cl>[Pt]=O.O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:27][CH2:26][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][C:16]([C:22]([F:25])([F:23])[F:24])=[CH:15][CH:14]=4)[CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccncc3)CC12
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCC3CCNCC3)CC12

Procedure:
A mixture of 5 g. (0.014 mole) of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 60 ml. of ethanol, 120 ml. of water, 12 ml. of concentrated hydrochloric acid and 1 g. of platinum oxide catalyst was hydrogenated in a Parr apparatus for 2 hours. The catalyst was filtered and the solvents removed. The residue was crystallized two times from methanol to yield 42 g. of the title compound as the dihydrochloride salt, m.p. 279°-282° C.
Reaction SMILES: [O:1]1[C@@H:21]2[C@:2]31[C@H:11]([C@H:12]1[C@:19]([CH3:22])([CH2:20]2)[C@@:15]([OH:23])([C:16](=[O:18])[CH3:17])[C@H:14]([CH3:24])[CH2:13]1)[CH2:10][C@H:9]([F:25])[C:8]1[C@:3]3([CH3:27])[CH2:4][CH2:5][C:6](=[O:26])[CH:7]=1.[FH:28]>>[F:25][C@@H:9]1[C:8]2[C@:3]([CH3:27])([CH2:4][CH2:5][C:6](=[O:26])[CH:7]=2)[C@:2]2([F:28])[C@H:11]([C@H:12]3[C@:19]([CH3:22])([CH2:20][C@@H:21]2[OH:1])[C@@:15]([OH:23])([C:16](=[O:18])[CH3:17])[C@H:14]([CH3:24])[CH2:13]3)[CH2:10]1
Reactant: CC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Reactant: F
Product: CC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
The epoxide ring of the 9β,11β-epoxy-6α-fluoro-17α-hydroxy-16α-methyl-4-pregnene-3,20-dione is opened by means of hydrogen fluoride, and 6α,9α-difluoro-11β,17 -dihydroxy-16α-methyl-4-pregnene-3,20-dione is obtained. The conditions under which this reaction step is performed are also conventional (J. Fried et al. Organic Reactions in Steroid Chemistry, van Nostrand Reinhold Co., New York et al., Vol. 1, 1972, 425 ff).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH2:15][C:16](CC3(C)COC(C4C=CC(F)=CC=4)OC3)=O)([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:39]1CCCC1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH3:14])([CH:15]([CH3:16])[OH:39])[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC1(CC(=O)CC2(C)COC(c3ccc(F)cc3)OC2)COC(c2ccc(F)cc2)OC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)C1(C)COC(c2ccc(F)cc2)OC1

Procedure:
2-(p-Fluorophenyl)-5-methyl-1,3-dioxan-5-yl-methyl ketone (11.85 g) in dry ether (100 ml) was added to a slurry of lithium aluminium hydride (2.5 g) in dry ether (50 ml) and the mixture was heated under reflux for 4 hours. Moist tetrahydrofuran (20 ml) was added and the mixture was filtered. The filtrate was concentrated and the crude product was recrystallised from ethyl acetate/light petroleum (b.p. 60°-80°) as white crystals, m.p.78°, of the pure cis isomer.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:4]=2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:8]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>>[Cl:26][C:24]1[CH:25]=[CH:3][C:4]2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:19]=3)[N:8]=[C:2]([N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]3)[C:22]=2[CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(Cl)c2cc(Cl)ccc21
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21

Procedure:
5,7-Dichloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (170 mg, 0.44 mmol) and tert-butyl piperidin-4-ylcarbamate (89 mg, 0.44 mmol) were coupled according to the corresponding procedure described in Example 14 to yield intermediate tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate. (85 mg, 35%). Tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate (85 mg, 0.16 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at ambient temperature for 2 hours. The solution was concentrated, redissolved in ethyl acetate and extracted into 1 M aqueous hydrochloric acid (3×10 mL). The extracts were neutralized with saturated sodium bicarbonate, extracted with dichloromethane (3×25 mL), then dried with sodium sulfate, filtered, and concentrated to yield 5-(4-aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (20 mg, 29% yield). MS (M+H)+447.2.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8]O)[N:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:8][N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:11])([F:10])[F:1])=[N:4]1
Reactant: OCn1ccc(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.33 g of 3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol was dissolved to 40 ml of dichloromethane. 2.7 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.44 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:23](=[O:25])[CH3:24])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.54 g, 2.42 mmol) in DCM (5 ml) at 0° C. was added pyridine (0.23 ml, 2.9 mmol). The reaction mixture was cooled to 0° C. and a solution of acetyl chloride (0.21 ml, 2.9 mmol) in DCM (4 ml) was added drop wise over 5 min. The reaction mixture was stirred at r.t. for 18 hrs, quenched with water (10 ml) and extracted in DCM (2×20 ml). The organic layer was dried over Na2SO4 and concentrated to afford the crude oil (0.64 g) which was used for the next step without purification.