Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]([S:33]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[CH3:44])(=[O:35])=[O:34])[CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]([C:19]1[N:20]([S:33]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[CH3:44])(=[O:34])=[O:35])[CH:21]=[C:22]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:3]=2)[CH:23]=1)=[O:18]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: Cc1cnc(-c2ccccc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(-c2cc(-c3ccccc3)ncc2C)cn1S(=O)(=O)c1c(C)cc(C)cc1C

Procedure:
13 (29 mg, 0.12 mmol, 1.0 equiv.) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2,4,6-trimethylbenzensulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (52 mg, 0.12 mmol, 1.0 equiv.) were dissolved in benzene (1.2 mL). After adding aqueous Na2CO3 (0.2 mL), Pd(PPh3)4 (28 mg, 0.024 mol, 0.2 equiv.) was then added and the resulting mixture was refluxed for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. After drying the organic layer over Na2SO4, the solvent was removed under reduced pressure. The crude product 14 was used without further purification (100 mg, HPLC Rt=7.005 minutes, ES+ 475.4, ES− not observed).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=O)[C:4]2=[CH:3][CH:2]=1)=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]2[CH2:7][C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[CH2:10]2)[CH:19]=[CH:20][CH:21]=1
Reactant: NNC(=O)Nc1cccc(F)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=C1Cc2ccccc2C1)Nc1cccc(F)c1

Procedure:
ninhydrin, 4-(3-fluorophenyl)-semicarbazide hydrochloride
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.O1CCOCC1.[ClH:38]>>[ClH:38].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(F)ccc2OC)cc1
Reaction time: 1 h

Procedure:
A solution of (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate, (2.86 g, 6.62 mmol) in 4M HCl in 1,4-dioxane (33.1 ml, 132 mmol) is stirred at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride salt (2.44 g). HPLC retention time=1.46 minutes (condition A); MS (m+1)=332.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (t, J=6.4 Hz, 3H) 2.66-2.77 (m, 1H) 2.78-2.91 (m, 1H) 2.94-3.10 (m, 1H) 3.42-3.53 (m, 1H) 3.67 (s, 3H) 3.83-3.96 (m, 1H) 4.07 (q, J=6.8 Hz, 2H) 6.77-6.84 (m, 1H) 6.87-6.96 (m, 2H) 7.23 (d, J=7.1 Hz, 2H) 7.38 (d, J=7.1 Hz, 2H) 8.64 (br. s., 2H)
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[ClH:12].N([O-])=O.[Na+]>>[Cl:12][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Nc1cccc2cnccc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1cccc2cnccc12

Procedure:
5-Aminoisoquinoline is reacted with hydrochloric acid, sodium nitrite and cuprous chloride to afford 5-chloroisoquinoline, which was then reduced with diborane in tetrahydrofuran. The resultant 5-chlorotetrahydroisoquinoline was then acetylated with acetic anhydride and chlorosulfonated with chlorosulfonic acid at low temperature, for example -50° C., to afford the desired chlorosulfonyl tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30]([OH:32])=O)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.Cl.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:56][C:57]([F:61])([F:60])[CH2:58][NH:59][C:30]([CH:28]1[CH2:29][N:26]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH2:12][C:11]([C:17]4[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=4)([C:13]([F:15])([F:16])[F:14])[O:10][N:9]=3)=[CH:7][C:2]=2[Cl:1])[CH2:27]1)=[O:32]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
To a stirred solution of 1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.190 mmol) in dry DMF (3 mL) was added EDCl.HCl (0.055 g, 0.280 mmol), DIPEA (0.049 g, 0.380 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.190 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL), white solid was precipitated out, and solid was filtered, dried. Solid was purified by preparative TLC to afford off white solid (0.045 g, 41%). 1H-NMR (400 MHz, CDCl3) δ: 3.38-3.42 (m, 1H), 3.60 (d, 1H, J=17.08 Hz), 3.93-4.03 (m, 3H), 4.26-4.36 (m, 4H), 5.95 (t, 1H), 6.49 (d, 1H, J=8.52 Hz), 7.42 (dd, 1H, J1=8.56 Hz, J2=1.88 Hz), 7.47 (d, 1H, J=1.84 Hz), 7.62 (s, 2H); LC-MS (m/z): [M−H] 605.40.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)=[C:4]([F:9])[CH:3]=1
Reactant: O=C1CCC1
Reactant: Fc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2F)CCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A 100 mL 3-neck round bottom flask was charged with 4-bromo-2-fluoro-1-iodobenzene (1000 mg, 3.32 mmol) and diethyl ether (30 mL). The solution was cooled to −78 °C., and n-butyllithium (1.329 mL, 3.32 mmol) was added dropwise, keeping the temperature below −68° C. After stirring for 15 min, cyclobutanone (0.249 mL, 3.32 mmol) was added dropwise, keeping temperature; below −68° C. The solution was stirred at −78° C. for 15 min. The reaction was then quenched by the addition of saturated ammonium chloride (25 mL). The layers were separated, and the organic was washed with water (1×10 mL) and brine (1×10 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue Was purified by flash chromatography (SiO2 gel), eluting with 3% ethylacetate/hexanes to give the desired product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.69 (m, 1 H), 1.91-2.05 (m, 1 H), 2.19-2.28 (m, 2 H), 2.46-2.55 (m, 2 H), 5.59 (s, 1 H), 7.33-7.40 (m, 2 H), 7.44-7.48 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH3:28]>>[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])(=[O:26])[NH2:28]
Reactant: N
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: NC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with ammonia at 22° C. to give the title compound as a white solid. MS: 375.1 ([M−H]−).
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:5]1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]=[C:29]1S(C)(=O)=O.O>CN(C=O)C>[F:21][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:29]3[N:28]([CH2:27][CH2:26][O:25][CH3:24])[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[N:30]=3)=[CH:16][CH:15]=2)=[N:5]1
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cc(F)cnc23)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(-c3nn(CC(F)F)c4cc(F)cnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a stirred solution of 4-[1-(2,2-difluoroethyl)-6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (47 mg) in DMF (4 mL) was added NaH (60% in oil, 4.23 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (32.0 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1.[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=3)[N:6]=2)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1

Procedure:
The title compound was prepared from 2-amino-4-(-3-nitrophenyl)thiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (36.0 mg) with purity >90%. MS (pos) m/z 410.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:11][CH2:12][CH2:13]Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:11][CH2:12][CH2:13][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(SCCCl)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: Clc1ccc(C2=NOCCS2)cc1

Procedure:
2-Chloroethyl 4-chloro-N-hydroxybenzenecarboximidothioate (2.5 g, 0.01 mol) was cyclised with sodium (0.23 g) in ethanol (25 ml) as described in Example 2. 3-(4-Chlorophenyl)-5,6-dihydro-1,4,2-oxathiazine, mp 80.5°-81.5° C., was isolated. (Found: C, 50.16; H, 4.24; N, 6.44. C9H8ClNOS requires C, 50.58; H, 3.77; N, 6.55.)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH:38][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([CH:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]4)=[CH:20][CH:19]=3)[NH:36][N:37]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COCCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 34.9 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[1-(2-methoxyethyl)piperidin-4-yl]benzamide was prepared following the procedure as outlined for Example 99, starting from methyl 4-(1-(2-methoxyethyl)piperidin-4-yl)benzoate (0.428 g, 1.25 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.309 g, 1.25 mmol) and 2M trimethylaluminium (1.56 mL, 3.13 mmol) in toluene (10 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product was crystallised from DCM/diethyl ether to afford the title compound (0.215 g, 34.9%) as an off white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][NH2:13]>O>[CH3:12][NH:13][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: CN
Reactant: ClCc1cc2ccccc2o1
Solvent: O
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
2-(Chloromethyl) benzofuran (2.77 g, 16.63 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a nitrogen atmosphere. After 10 minutes, the reaction mixture was warmed to room temperature and stirring was continued for 72 hours. The mixture was diluted with water and extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (10% methanol/dichloromethane) to afford 1.00 g (37%) of pure product as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1>O>[CH3:17][C:18]1[O:19][C:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2)o1
Reaction time: 0.5 h

Procedure:
Into a flask containing benzoyl chloride (206 g) and dichloromethane (2 L) was added aluminum chloride (200 g) while stirring. After 30 minutes at ambient temperature the flask was placed in a water bath and a condenser was connected through which 2-methylfuran (210 mL) was added dropwise over 30 minutes. The resulting mixture was stirred for 7 hours then carefully poured into cold water (3 L). The organic layer was collected, washed with water and concentrated to afford (5-methylfuran-2-yl)(phenyl)methanone as an oily product (220 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][C:13](=O)[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.CO>O1CCCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2c(c1)C[C@H](NC[C@@H](O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 3 g of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide, SR 58588, described in Example 8(b), in 40 ml of anhydrous tetrahydrofuran, heated with reflux under nitrogen stream, there is added 2.7 ml of a 10M solution of boranemethylsulfide in 20 ml of tetrahydrofuran, and the refluxing is maintained for 4 hours. To the solution cooled to room temperature, there is added 25 ml of methanol and the reaction mixture is left under stirring at first at room temperature for 30 minutes and then at reflux for 30 minutes. The solution is concentrated under reduced pressure and, after filtration, the product is crystallized twice from isopropanol. There is obtained 2.1 g (73%) of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine, SR 58590; m.p. 186°-188° C.; [alpha]=+76° (methanol, c=0.5%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC(NC(=O)CC[C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][N:46]=[C:45]([C:49]#[N:50])[CH:44]=3)=[CH:38][CH:37]=2)=CC=1>>[Si:1]([O:8][CH2:9]/[C:10](=[CH:24]\[C:37]1[CH:36]=[CH:41][CH:40]=[C:39]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:49]#[N:50])[CH:44]=2)[CH:38]=1)/[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)Nc1cccc(C(C)(C)C)c1
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)cc3)cc2)ccn1
Product: CC(C)(C)c1cccc(NC(=O)/C(=C/c2cccc(Oc3ccnc(C#N)c3)c2)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
The title compound was prepared as described in Example 36, Step 2, using 2-((tert-butyldimethylsilyloxy)methyl)-N-(3-tert-butylphenyl)acrylamide and 4-(3-iodophenoxy)picolinonitrile (prepared as described in Example 11, Step 1 using 3-iodophenol and 4-chloropicolinonitrile). LCMS, FA: Rt=2.61 min, [MH+542.0].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[H][H]>CO.[Pd]>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[NH2:12]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(F)c(N)c1
Yield: 80.4 %

Procedure:
A mixture of 4-fluoro-3-nitrophenyl methyl sulfone (ABCR; 1.50 g; 6.84 mmol) and 10% Pd/C (100 mg) in MeOH (30 ml) was placed in a PARR reactor and treated with a pressure of 15 atm of hydrogen for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to dryness affording the title compound (1.04 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.2 %

Procedure:
A suspension of 0.193 g (0.51 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 2 ml of N,N-dimethylformamide was treated with 0.26 g (2.55 mmol) of dipropylamine. After stirring at room temperature for 17 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 39:1 as the eluent. The product was recrystallized from ether/n-hexane at 0°. There were obtained 0.094 g (41%) of 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 128°-130°.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:11][C:12]([F:14])=[CH2:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9].C(O)=O.[Cl-].[Na+]>O>[F:14][C:12](=[CH2:13])[CH2:11][N:5]([CH2:4][CH:3]=[O:2])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: C=C(F)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C=C(F)CN(CC=O)C(=O)OCC

Procedure:
14.1 g (60 mmol) of ethyl N-(2,2-dimethoxyethyl) -N-(2-fluoroallyl)-carbamate are heated under reflux for three hours with 6.3 ml of formic acid in 120 ml of water. The solution is saturated with sodium chloride and extracted several with methylene chloride, the organic solutions are washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([O:15][C:16]([F:19])([F:18])[F:17])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.ClCCCl.[Na]>O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)=[C:9]([O:15][C:16]([F:19])([F:18])[F:17])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A 40 mL vial was charged with 4-(morpholin-4-yl)-2-(trifluoromethoxy)benzaldehyde (400 mg, 1.45 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (270 mg, 1.45 mmol, 1.00 equiv), 1,2-dichloroethane (15 mL). The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyhydroborate (925 mg, 4.36 mmol, 3.00 equiv) was added. The resulting solution was stirred for 15 hours at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 15 mL of water. The resulting solution was extracted with dichloromethane (3×15 mL) and the organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 590 mg (91% yield) of tert-butyl 4-[[4-(morpholin-4-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 446 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:21])[N:11]=[C:10]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:9]=23)[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.O.[Ni](Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:21])[N:11]=[C:10]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:9]=23)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc2c(cnn2CC)c1-c1cncc(Br)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCc1c(C)nc2c(cnn2CC)c1-c1cncc(Br)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To a solution of ethyl (2E)-3-[4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (47 mg) in MeOH (2 ml) was added nickel chloride hexahydrate (7.26 mg) and sodium borohydride (10.7 mg) at −10° C. and the mixture was stirred at −10° C. for 15 minutes. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of EtOAc and n-hexane (1:1.5) to give ethyl 3-[4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (12 mg) as a light yellow oil.