Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH:2]1[CH:3]([OH:33])[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]1[OH:8]
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC1C(O)CC(CO)C(O)C1O
Reaction time: 8 h

Procedure:
To a solution of Intermediate B (86.5 mg, 0.194 mmol) in MeOH (3 mL) and acetic acid (1 mL) was added Pd/C (10%, 102 mg, 0.097 mmol). The mixture was hydrogenated at 50 psi and at room temperature for 8 h. Catalyst was removed by filtration and solvents were evaporated under reduced pressure to give the product rac-(1R,2R,3S,4S,6R)-3-amino-6-(hydroxymethyl)cyclohexane-1,2,4-triol as the acetic acid salt (46 mg, 100%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 4.07 (brs, 1H), 3.66-3.58 (m, 3H), 3.20 (t, J=9.5 Hz, 1H), 2.85 (brs, 1H), 1.93-1.85 (m, 2H), 1.86 (s, 3H), 1.42 (t, J=13.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1
Reaction time: 4 h

Procedure:
4′-Fluorobiphenyl (5 g) was dissolved in chloroform (100 mL) at room temperature. Chlorosulfonic acid (5 g) was added dropwise and stirring was continued for a further 4 hours, after which the solvent was allowed to slowly evaporate until precipitation was seen. The mixture was left to recrystallised overnight and the solid was collected by filtration. Further crops of crystals were collected from the filtrate.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[OH:18])=[O:2].[OH-].[K+].S(OC)(O[CH3:25])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:14])([CH3:15])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[O:18][CH3:25])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C)c2c1C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
Methylation. 2-Formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (42 g, 0.17 mol) was stirred with toluene (656 mL), and potassium hydroxide 85% (16.8 g, 0.255 mol) was added in one portion. The mixture was heated to 40° C., dimethyl sulfate (32.13 g, 0.255 mol) added at 40°-45° C. during 0.5 h, and the heating continued at 50° C. for an additional 1.5 h. The mixture was cooled to 20° C., neutralized with 5% HCl solution, then washed with water (20 mL), and finally washed with brine (25 mL). The solvent was removed by distillation and the residue distilled to give 2-formyl-1-methoxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (36 g), bp 140°-142° C./1.5 mm, GLC purity 95%. Crystallization from hexane gave 28 g material, GLC purity 99%. 1H-NMR (CDCl3) δ10.23 (2H, s), 7.41 (1H, s), 3.89 (3H, s), 2.52 (3H, s), 1.63 (4H, s), 1.42 (6H, s), 1.40 (6H, s). 13C-NMR (CDCl3) δ189.9 (1C, d), 162.3 (1C, s), 153.1 (1C, s), 139.9 (1C, s), 132.7 (1C, s), 131.3 (1C, d), 126.5 (1C, s), 66.0 (1C, q), 39.4 (1C, t), 38.2 (1C, t), 36.4 (1C, s), 35.6 (1C, s), 30.0 (2C, q), 28.9 (2C, q), 23.7 (1C, q). IR (KBr) 1683, 1235 cm-1, MS (m/e) 260.3 (M+, 46.3), 245.2 (100.0), 175 (38.5), 128 (31.1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[NH2:44][C:30]1[N:31]=[CH:32][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:34][C:29]=1[F:28]
Reactant: CC1(C)OB(c2cnc(N)c(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Nc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to afford a white amorphous powder. HPLC (Condition 4) tR=4.37 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=478.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.89 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.18-3.28 (m, 2H) 3.34-3.47 (m, 1H) 4.19 (br. s, 1H) 4.83 (d, J=3.13 Hz, 1H) 6.32 (s, 2H) 7.32 (d, J=8.99 Hz, 2H) 7.40 (d, J=11.73 Hz, 1H) 7.77 (s, 1H) 7.83 (d, J=8.99 Hz, 2H) 7.93 (m, J=2.30, 1.20 Hz, 1H) 8.64-8.72 (m, 1H) 10.11 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:30][NH:31][CH3:32].C1COCC1>>[CH3:30][N:31]([CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:32]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(CCl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Compound 478 (340 mg, 0.789 mmol) was added to a 2 mol/L solution of dimethylamine in THF (20 mL, 39.5 mmol), followed by stirring overnight at 60° C. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by reslurrying with a mixed solvent of ethanol and diethyl ether to afford the entitled Compound 479 (153 mg, 44%) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.CO.Cl.[O-:16][C:17]#[N:18].[K+]>O>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:17]([NH2:18])=[O:16]
Reactant: CNC1CCCc2ccccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C(N)=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 8.05 grams (0.05 mole) of 1,2,3,4-tetrahydro-N-methyl-1-naphthylamine in 10 ml. of methanol is added a solution of 4.2 ml. of 12N hydrochloric acid (0.05 mole) in 35 ml. of water. The mixture is cooled in an ice-water bath while a solution of 4.46 grams (0.055 mole) of potassium cyanate in 15 ml. is added dropwise. After the addition is complete, the reaction mixture is stirred at room temperature for 45 minutes and then at 70°C. to 75°C. for 30 minutes. The mixture is cooled to 25°C., and the solid product filtered off, washed with water and then with cold ethyl acetate. The dried product weighs 7.1 grams and has melting point 160°-163°C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161°C. to 163°C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161°C. to 163°C. Analysis Calculated for C 12 H16N2O: C, 70.56; H, 7.90; N, 13,72. Found: C, 70.60; H, 7.94; N, 13.75.
Reaction SMILES: [C:1]([C:5]1([CH:11](C)[CH3:12])[CH:9]=[CH:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([C:5]1([CH2:11][CH3:12])[CH2:9][CH2:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C=CC(C(C)C)(C(C)(C)C)O1
Agent: [Pd]
Product: CCC1(C(C)(C)C)CCC(C)O1
Yield: 109.1 %

Procedure:
Analogous to the procedure of example 2, by hydrogenation of 3.12 g (18.4 mmol) of 2-tert-butyl-2-isopropyl-5-methyl-2,5-dihydrofuran in the presence of 1.20 g (1.12 mmol) of 10% palladium on activated charcoal. Kugelrohr distillation of the reaction product provided at 70-80° C./20 mbar 3.42 g (93%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:10])[CH:6]([OH:9])[CH2:7][OH:8])=[N+:2]=[N-:3].CO[C:13](OC)([CH3:15])[CH3:14].S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O>[N:1]([CH2:4][CH:5]([CH:6]1[CH2:7][O:8][C:13]([CH3:15])([CH3:14])[O:9]1)[OH:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(O)C(O)CO
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC1(C)OCC(C(O)CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 14.71 g of 4-azido-1,2,3-butanetriol in 30 ml of acetone is combined with 13.95 g of 2,2-dimethoxypropane, as well as 0.1 ml of concentrated sulfuric acid. The mixture is stirred overnight at room temperature, neutralized with 2N sodium hydroxide solution, and concentrated to dryness under vacuum. The residue is distilled with a water-jet aspirator. 2-Azido-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol passes over as a colorless oil at 130°-132° C./13 mm. Yield: 11.79 g (63% of theory).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[NH2:5][C:6](=[O:37])[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH2:19][C:20]([OH:22])=[O:21])[N:11]([CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[C:10]=1[CH3:36])=[O:8].[Na].C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:2]([O:22][C:20](=[O:21])[CH2:19][O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([C:7](=[O:8])[C:6]([NH2:5])=[O:37])=[C:10]([CH3:36])[N:11]2[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Br
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OC(C)C)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flask containing 15 ml of dimethylformamide was added with stirring 0.11 ml of 2-bromopropane and 500 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The reaction mixture was stirred at room temperature overnight. The reaction was incomplete. Thereafter, 180 mg of KI was added and the mixture was heated. After 24 hours the reaction mixture was poured into 50 ml of saturated NaHCO3 and extracted with ethyl acetate. The EtOAc solution was washed with water, dried over Na2SO4, and concentrated at reduced pressure. The title compound was then crystallized from EtOAc/hexane.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:32])=[O:5])[CH2:3][CH2:2]1.[N+:33]([C:36]1[CH:37]=[N:38][NH:39][CH:40]=1)([O-:35])=[O:34].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12]([N:38]4[CH:37]=[C:36]([N+:33]([O-:35])=[O:34])[CH:40]=[N:39]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:32])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]1CCc2c(ccc(-n3cc([N+](=O)[O-])cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A 100-mL round-bottom flask equipped with a balloon filled with air was charged with (5)-cyclopropyl(2-methyl-5-phenoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.240 g, 0.55 mmol), 4-nitro-1H-pyrazole (0.188 g, 1.66 mmol), copper (II) acetate (0.301 g, 1.66 mmol), pyridine (0.2 mL), and N,N-dimethylformamide (5 mL), and the resulting mixture stirred overnight at 90° C. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (eluting with 1:3, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.060 g, 26%) as yellow oil. MS (ESI, pos. ion) m/z 419 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)c(F)c1F
Solvent: ClCCl
Product: Fc1c(Br)ccc(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-bromo-2,3-difluorophenol (1.0 g, 0.0048 mol), phenylboronic acid (1.4 g, 0.012 mol), TEA (4.0 mL, 0.029 mol), cupric acetate (1.4 g, 0.0076 mol) and DCM (60 mL, 1 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.70 (ddd, J=9.22, 7.33, 2.15 Hz, 1H), 6.95-7.02 (m, 2H), 7.15 (t, J=7.45 Hz, 1H), 7.23 (ddd, J=9.16, 6.88, 2.40 Hz, 1H), 7.31-7.38 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][C:25]([F:24])([F:35])[F:36])[CH:28]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C(F)(F)F)c2)nc1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: CCc1cnc(N(CCc2ccc(O)c(C(F)(F)F)c2)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-{2-[4-methoxy-3-(trifluoromethyl)phenyl]ethyl}pyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7](O)[C:6]([CH3:11])=[CH:5][N:4]=1.P(Br)(Br)([Br:14])=O.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:14][C:7]1[C:6]([CH3:11])=[CH:5][N:4]=[C:3]([CH2:2][Cl:1])[C:8]=1[CH3:9]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cnc(CCl)c(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cnc(CCl)c(C)c1Br
Temperature: 130 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A neat mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8.2 g, 47.8 mmol) and POBr3 (60 g, 209 mmol) was stirred at 130° C. for 3 h. The resulting viscous oil was cooled to r.t. and poured onto ice water. The pH was adjusted to 10 with solid KOH. Work-up (CHCl3), drying (MgSO4) and evaporation afforded the title compound as a purple solid (8.7 g, 78% yield) which was used without purification. HPLC Rt: 6.028 min. 1H-NMR (CDCl3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: FC1C=CC2N=C([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)SC=2C=1.Cl[C:30]1[S:31][C:32]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[NH:23]1[CH2:22][CH2:21][CH:20]([N:18]2[CH:19]=[C:15]([C:13]3[CH:14]=[C:9]([C:30]4[S:31][C:32]5[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:33]=5[N:34]=4)[C:10]([NH2:26])=[N:11][CH:12]=3)[CH:16]=[N:17]2)[CH2:25][CH2:24]1
Reactant: FC(F)(F)c1cccc2nc(Cl)sc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(C(F)(F)F)c2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-7-trifluoromethyl-1,3-benzothiazole in place of 2-chloro-6-fluoro-1,3-benzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.12-2.31 (m, 4H), 3.05-3.18 (m, 2H), 3.41 (d, J=12.8 Hz, 2H), 4.47-4.57 (m, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 8.12 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 8.57 (s, 1H), 8.60 (d, J=2.2 Hz, 1H). MS (ES+): m/z=445.08 [MH+]. HPLC: tR=2.38 min (ZQ2, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=5)[C:6]=4[CH:17]=3)=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (28 mg, 21%), MS (ISP) m/z=389.4 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (84.0 mg, 378 μmol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]=2[CH:13]=1.[CH3:14][N:15](C)C=O>C(N)CN.O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)CNc2cc(Br)ccc2O1
Reactant: CN(C)C=O
Solvent: O
Solvent: NCCN
Product: CC1(C)CNc2cc(C#N)ccc2O1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 480 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine, 206 mg of cuprous cyanide and 5 ml of N,N-dimethylformamide was stirred at 130° C. for 4 hours and further at 150° C. for 5 hours. This reaction mixture was diluted with 0.5 ml of ethylenediamine and 10 ml of water and extracted with benzene. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with ethyl acetate-hexane (10:1). The crude crystals from the eluate were washed with hexane and dried to give 160 mg of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine. This compound has the following physicochemical properties.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH3:32][C:33]1([CH3:39])[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1>>[CH3:32][C:33]1([CH3:39])[N:34]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[CH2:35][CH2:36][N:37]([C:27]([C@@H:11]2[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:38]1
Reactant: CC1(C)CNCCN1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: CC1(C)CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 106 %

Procedure:
Following a procedure similar to that described in Preparation 38, but using 0.35 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.15 g of N,N'-carbonyldiimidazole and 0.13 g of 2,2-dimethylpiperazine, 250 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20](OCC)=[O:21]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:20](=[O:21])[O:11][C:5]=2[CH:4]=1
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: COc1ccc(O)cc1OC
Agent: Cl
Agent: O=S(=O)(O)O
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Temperature: 0 °C
Yield: 75.5 %

Procedure:
Prepared by the method described in Example 1 except that the 3,4-dimethoxyphenol (61.5 g, 0.40 moles) is added in one portion to an ice-cooled mixture of ethyl 4-oxo-3-piperidinecarboxylate hydrochloride (75 g, 0.36 moles) and 200 ml of 72% sulfuric acid. Recrystallization from acetonitrile yielded the product (71 g), mp 186°-188° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C@@:6]1([CH2:24][CH3:25])[C@@H:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[C:14]=32)[CH2:9][CH2:8][CH2:7]1)[CH3:5].[OH-].[K+]>C(O)C>[CH2:24]([C@:6]1([CH:4]([CH3:5])[C:3]([OH:26])=[O:2])[C@@H:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[C:14]=32)[CH2:9][CH2:8][CH2:7]1)[CH3:25]
Reactant: CC[C@@]1(C(C)C(=O)OC)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@]1(C(C)C(=O)O)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Yield: 66 %

Procedure:
The solution of 10.0 g. (0.028 moles) of (-)-(1S,12bS)-1-ethyl-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl-propionic acid methyl ester (prepared as described in Example 48) in 200 ml. of 96% of ethanol containing 2.5 g. (0.044 moles) of potassium hydroxide is refluxed for one hour. After cooling down, the solution is evaporated to dryness, the evaporation residue is dissolved in a little amount of water and acidified to pH 6 by adding acetic acid. The precipitated product is filtered, washed with water and dried to give 6.28 g. (66.0% yield) of the title compound with an Rf value of 0.51 (Polygram SIL G/UV254 ; developed by an 5:1 mixture of isopropanol with 25% aqueous ammonia solution; detected by UV light).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])C#N.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+]>O.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:12]([OH:13])=[O:15]
Reactant: COc1ccc(C#N)cc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)cc1F
Yield: 90 %

Procedure:
3-Fluoro-4-methoxybenzonitrile (2.0 g, 13.2 mmol) in water (5 mL) and concentrated sulphuric acid (5 mL) was heated at 110° C. for 4 hours. The solution was then cooled to room temperature and neutralized with solid sodium carbonate. Acidification with glacial acetic acid leads to a white precipitate, which was collected by filtration and dissolved in dichloromethane. The resulting solution was dried over sodium sulfate, filtered, and concentrated to give the product as a beige-colored solid (2.03 g, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]([CH3:23])[C:20](O)=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]([CH3:23])[C:20]([Cl:27])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Cl)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-benzyloxy-5-trifluoromethyl-phenyl)-propionic acid (1.4 g, 4.0 mmol) in CH2Cl2 was added oxalyl chloride (0.76 mL, 8.0 mmol), followed by 3 drops of DMF. After stirring for 15 minutes at room temperature, the mixture was concentrated to give the title compound.