Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reaction time: 1.75 h

Procedure:
To acetic anhydride (80 mL) was added at rt 2-amino-5,6-dihydro-4H-benzothiazol-7-one (10 g, 59.4 mmol) and the yellow suspension was heated to reflux. After 1.75 h stirring at this temperature, the RM was allowed to cool with stirring, and stirred overnight at rt. After further cooling with an ice/NaCl bath, the suspension was filtered. The solid was then refluxed twice with acetone (10 mL then 15 mL) and filtered. The resulting solid was dried under vacuum at 40° C. overnight to afford the title compound as a beige solid (HPLC: tR 3.47 min (Method A3), M−H=211.1), 1H-NMR in DMSO-d6 (600 MHz): 12.55 (s, br, 1H); 2.84 (t, 2H); 2.48 (t, 2H); 2.17 (s, 3H); 2.065 (qt, 2H)).
Reaction SMILES: O.[CH3:2][N:3]([CH3:36])[C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[C:11]([O:34][CH3:35])[CH:10]=2)[CH2:5]1.[NH4+].[Cl-]>[Fe].C(O)C>[CH3:36][N:3]([CH3:2])[C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([O:34][CH3:35])[C:12]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:13][C:14]=2[NH2:15])[CH2:5]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Reaction time: 3 h
Yield: 117.2 %

Procedure:
Water (4 mL) was added to a stirred mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 165, 286 mg, 0.60 mmol), iron (202 mg, 3.62 mmol), NH4Cl (22.6 mg, 0.42 mmol) and ethanol (24 mL). The resulting mixture was stirred at 105° C. for 3 h and was then filtered through diatomaceous earth (Celite™) and concentrated in vacuo. Part-purification by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia gave the title compound (312 mg, 116%) as a brown gum, which was used without further purification; 1H NMR: 2.13 (2H, d), 2.32 (2H, d), 2.80 (6H, d), 2.87-2.98 (2H, m), 3.19 (2H, d), 3.77 (3H, s), 6.74 (1H, s), 7.17 (4H, ddd), 7.46 (1H, d), 7.56 (1H, s), 7.77 (1H, s), 8.28 (2H, dd), 8.43 (1H, d), 11.76 (1H, s); m/z: ES+ MH+ 444.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@H:28]([O:29]CC3C=CC=CC=3)[C@@H:27]([O:37]CC3C=CC=CC=3)[C@H:26]([O:45]CC3C=CC=CC=3)[C@@H:25]([CH2:53][O:54]CC3C=CC=CC=3)[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+].[H][H]>C(OC(=O)C)(=O)C.CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([CH:23]2[CH:28]([OH:29])[CH:27]([OH:37])[CH:26]([OH:45])[CH:25]([CH2:53][OH:54])[O:24]2)=[CH:19][C:3]=1[CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(C#Cc2ccccc2)nn1
Reactant: [H][H]
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: OCC1OC(c2ccc(Cl)c(Cc3ccc(C#Cc4ccccc4)nn3)c2)C(O)C(O)C1O
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of 3-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-6-(phenylethynyl)pyridazine (0.5 mmol) from step 1 at −30° C. in acetic anhydride (10 mL) was slowly added a solution of trimethylsilyl trifluoromethanesulfonate (0.73 mL, 4.0 mmol) in acetic anhydride (5 mL). The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, cooled to 0° C., and quenched with saturated sodium bicarbonate. After dilution with ethyl acetate, the organic layer was washed with sodium bicarbonate and brine prior to drying over magnesium sulfate. Filtration and removal of volatiles under reduced pressure yielded peracetylated compound as a brown amorphous solid. Deacetylation was achieved by addition of sodium methoxide (25 wt % in methanol, 1 mL) to a solution of this residue in methanol (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. Amberlite® IR120 hydrogen form was then added to neutralize the reaction mixture. The resin was filtered off and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (41 mg, 0.10 mmol, 25%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:23]=[CH:24][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:46])=[N:9]2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:23]=[CH:24][NH:25][CH:26]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:46])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3c[nH]cn3)ccc12
Reaction time: 0.5 h

Procedure:
To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(triphenylmethyl)imidazol-4-yl]but-3-yn-2-ol (45 mg, 0.07 mmol) in DCM (2 ml) was added trifluoroacetic acid (0.4 ml). The reaction was allowed to stand at RT for 0.5 hr and then concentrated in vacuo. DCM (5 mL) and saturated aqueous sodium bicarbonate (2 mL) were added and the organics extracted (4×5 mL DCM extractions). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute, 0-10% methanol gradient in DCM) to surrender the title compound as a pale brown solid: 1H NMR (250 MHz, MeOD) delta 1.92 (3H, s), 2.58 (3H, s), 7.28-7.14 (2H, m), 7.39 (1H, dd, J=8.2, 1.2 Hz), 7.82-7.64 (2H, m), 8.19 (1H, d, J=5.8 Hz), 8.98 (1H, s); LC-MS: m/z=+360.05 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][N:11]2[C:10](=[O:13])[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12]2)=[CH:18][CH:19]=1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccc2)nn1CCc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A mixture of 6-phenyl-3(2h)-pyridazinone (306 mg, 1.78 mmol), 1-(2-bromo-ethyl)-4-fluoro-benzene (397 μl, 1.95 mmol), and potassium carbonate, −325 mesh (614 mg, 4.44 μmol) in DMF (5 mL) was stirred for 3 days at 23° C. The mixture was partitioned between CH2Cl2 (30 mL) and 5% NaHCO3 (15 mL). The aqueous was further extracted with CH2Cl2 (2×5 mL) and the combined organics was dried over MgSO4, and concentrated under reduced pressure To give a clear oil. MS (ESI pos. ion) m/z (MH+): 295. Calc'd exact mass for C18H15FN2O: 294. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.16 (t, J=7.53 Hz, 2 H) 4.47 (t, J=7.78 Hz, 2 H) 6.88-7.06 (m, 3 H) 7.15-7.25 (m, 2 H) 7.35-7.53 (m, 3 H) 7.59-7.74 (m, 3 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 32.60, 52.08, 114.07, 114.28, 124.73, 127.81, 128.32, 128.89, 129.01, 129.20, 129.27, 132.63, 132.67, 133.57, 143.32, 158.60, 159.33, 161.76.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][N:4]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1)[CH2:17][C:18]([F:19])([F:20])[F:21])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.104 g, 0.333 mmol) in CH2Cl2 (3 mL) at 0° C. was added Et3N (0.07 mL, 0.5 mmol), followed by MsCl (0.03 mL, 0.37 mmol). The resulting mixture was stirred 12 h, gradually warming to rt. The mixture was poured into 10% v/v HCl and the layers were separated. The organic layer was washed (sat'd NaHCO3, water, brine), dried over Na2SO4, filtered and concentrated to a colorless film (0.122 g), which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.8 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.7, 2.7 Hz, 1H), 4.43 (t, J=5.7 Hz, 2H), 4.10 (q, J=8.5 Hz, 2H), 3.95 (t, J=5.7 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15].F[C:19]1[C:20]([CH3:39])=[N:21][C:22]2[C:27]([N:28]=1)=[C:26]([C:29]1[NH:37][C:36]3[CH2:35][CH2:34][NH:33][C:32](=[O:38])[C:31]=3[CH:30]=1)[CH:25]=[CH:24][CH:23]=2>CS(C)=O>[CH3:11][O:12][CH2:13][C:14]([NH:17][C:19]1[C:20]([CH3:39])=[N:21][C:22]2[C:27]([N:28]=1)=[C:26]([C:29]1[NH:37][C:36]3[CH2:35][CH2:34][NH:33][C:32](=[O:38])[C:31]=3[CH:30]=1)[CH:25]=[CH:24][CH:23]=2)([CH3:16])[CH3:15]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: COCC(C)(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
Prepared according to Example 127, using DIPEA (264 μl, 1.519 mmol), (2-methoxy-1,1-dimethylethyl)amine hydrochloride (78 mg, 0.759 mmol, ChemBridge Corp., San Diego, Calif.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.2 mL) and stirring at 100° C. for 3 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) provided 2-(3-((2-methoxy-1,1-dimethylethyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (27 mg, 28.1%). 1H NMR (DMSO-d6) δ: 11.83-11.94 (m, 1H), 7.77-7.83 (m, 1H), 7.56-7.62 (m, 1H), 7.31-7.39 (m, 1H), 6.90-6.98 (m, 1H), 5.87-5.92 (m, 1H), 3.62-3.68 (m, 2H), 3.40-3.46 (m, 1H), 3.16-3.20 (m, 2H), 2.81-2.88 (m, 2H), 2.66-2.69 (m, 2H), 2.31-2.36 (m, 3H), 1.50-1.56 (m, 6H). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])[CH2:10]1)=[O:7])#[N:2].C([Sn]([N:46]=[N+:47]=[N-:48])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[NH:46]1[C:1]([C:3]2[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=2)[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[O:20][C:21]=3[CH3:22])[CH2:10]2)=[O:7])=[N:2][N:48]=[N:47]1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cccc(C#N)c2)C1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cccc(-c3nnn[nH]3)c2)C1
Temperature: 160 °C

Procedure:
0.06 g of cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-cyanobenzoate is dissolved in 5 ml of xylene, 150 μm of tributyltin azide are added and the mixture is heated under reflux at 160° C. for 24 hours. The reaction is terminated by addition of 1 ml of trifluoroacetic acid (in 1 ml of methanol), 3 ml of water are added and the mixture is extracted with ethyl acetate (2×10 ml). The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is then removed under reduced pressure. Purification by preparative HPLC gives 0.04 g of the desired cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl 3-(1H-tetrazol-5-yl)benzoate as an amorphous solid.
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:23]1[CH:28]=[CH:27][C:26](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:4]([N:11]1[CH2:12][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a solution of sodium hydride (60% in oil, 6.36 g) in DMF (100 mL) was added ethyl 1-benzyl-3-oxopiperidine-4-carboxylate monohydrochloride (19.0 g) at 0° C., and the mixture was stirred for 5 min. N-phenyl bis(trifluoromethanesulfonimide) (25.0 g) was added, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. To a mixture of the obtained residue in toluene (125 mL) and water (7.5 mL) were added dihydroxyphenylborane (5.82 g), potassium carbonate (4.40 g) and tetrakis(triphenylphosphine)palladium(0) (3.67 g), and the mixture was stirred under an argon atmosphere at 100° C. for 14 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogen carbonate and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (solvent gradient; 10→20% ethyl acetate/hexane) to give ethyl 1-benzyl-5-phenyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10.2 g) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:16]=[CH2:17])(O)[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[BrH:20]>C(O)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[CH:16][CH2:17][Br:20])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Br
Reactant: C=CC1(O)c2ccccc2CCc2cc(Br)ccc21
Solvent: CC(=O)O
Product: BrCC=C1c2ccccc2CCc2cc(Br)ccc21
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A suspension of the above alcohol (1.1 g, 3.49 mmol) in acetic acid (10 mL) was stirred and treated at 15° C. with 15% solution of hydrogen bromide in acetic acid (7 mL) over 15 min. The mixture was stirred at 15° C. for 30 min and then at laboratory temperature for 1.5 h and evaporated in vacuo. The rest of acetic acid was removed by addition of 40 mL xylene and evaporation in vacuo and the residue was chromatographed in a short column of silica gel Fluka 60 (50 g, benzene). The benzene solutions were evaporated in vacuo to yield 1.25 g (95%) of 2-bromo-5-(2-bromo-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:11](O)(=O)=O>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: [O-][I+2]([O-])O
Solvent: CC(=O)O
Product: Nc1ccc(I)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5.00 g (36.4 mmole) of 2-aminobenzoic acid, 100 ml of acetic acid and 3.56 g (14.0 mmole) of molecular iodine, 2.12 g (8.4 mmole) of a 70% by weight aqueous solution of iodic acid was added dropwise. After the reaction mixture was stirred at the room temperature for 3 hour, the reaction mixture was analyzed in accordance with the high performance liquid chromatography. The results of the reaction are shown in Table 1. It was shown by the values obtained by the analysis of the reaction mixture that the yield of 2-amino-5-iodobenzoic acid was 60% as calculated based on the amount of iodine atom (this result is shown in the parenthesis since this result is different from the yield of the isolated product). A relatively great conversion was obtained when iodic acid of the oxidizing agent was used as the iodinating agent. However, it was difficult that the selectivity of the object product as great as that obtained by using hydrogen peroxide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:25][N:15]([CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[NH:33])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)[C:16](=[O:24])[O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)carbamate (830 mg, 2.445 mmol) in ethanol (35 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (1395 mg, 4.89 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and sodium carbonate (sat) and extracted with dichloromethane. The combine organics were dried, filtered and concentrated, then chromatographed in 1:1 ethyl acetate in hexanes, then ethyl acetate, followed by 5% (2M NH3 in methanol) in 1:1 ethyl acetate dichloromethane, giving the desired phenyl methyl(3-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (630 mg, 1.404 mmol, 57.4% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.23-7.21 (m, 1H), 7.13-7.05 (m, 3H), 6.56 (m, 2H), 6.49 (brs, 1H), 6.25 (brs, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H), 3.23-3.19 (m, 2H), 3.06, 2.93 (2s, 3H), 2.69-2.64 (m, 2H), 1.89-1.81 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1Br
Product: CCOC(=O)/C=C/c1ccc(O)cc1Br
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed 2-bromo-4-hydroxybenzaldehyde (2.0 g, 9.95 mmol, 1.00 equiv), ethyl (triphenylphosphoranylidene)acetate (5.22 g, 14.98 mmol, 1.51 equiv), Tol (50 mL). The resulting solution was stirred overnight at 90° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column, eluting with ethyl acetate/petroleum ether (1:4). This resulted in 2.2 g (77%) of ethyl (2E)-3-(2-bromo-4-hydroxyphenyl)prop-2-enoate as a white solid.
Reaction SMILES: C([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:37])[CH2:5][C:6]([O:8]CC)=[O:7])(=O)C.Cl.O>O1CCOCC1>[C:6]([CH2:5][NH:4][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:37])([OH:8])=[O:7]
Reactant: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CC(=O)OCC)C(C)=O)c(F)c3)cc(=O)c12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCC(=O)O)c(F)c3)cc(=O)c12
Yield: 76.8 %

Procedure:
143 mg (0.276 mmol) of Compound 74 obtained in Example 74 was dissolved in 12 ml of dioxane, 8 ml of concentrated hydrochloric acid was added and the mixture was heated ar reflux for 10 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 95 mg (77%) of Compound 75.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[C:25]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:26]=[C:27]([F:29])[CH:28]=2)OC1>>[F:29][C:27]1[CH:28]=[C:23]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)[CH:24]=[C:25]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2cc(F)cc(-c3cccnc3)c2)OC1
Product: Fc1cc(-c2cccnc2)cc(-c2ccnc3nc(C(F)(F)F)ccc23)c1
Yield: 23.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 3-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-5-fluorophenyl]pyridine (80 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(3-fluoro-5-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (19 mg, 24%). δH (360 MHz, CDCl3) 7.24-7.63 (1H, m), 7.41-7.45 (1H, m), 7.48-7.52 (2H, m), 7.63 (1H, d, J 4.6), 7.86 (1H, d, J 8.8), 7.92 (1H, dt, J 8.1 and 1.9), 8.55 (1H, d, J 8.8), 8.69 (1H, dd, J 1.6 and 4.7), 8.90 (1H, d, J 1.8), 9.32 (1H, d, J 4.6). m/z (ES+) 370 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=O)[C:9]3[CH:13]=[C:14]([S:17][CH3:18])[CH:15]=[CH:16][C:8]=3[O:7][C:6]=2[CH:19]=1.[Cl-:20].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:20][CH:10]1[C:9]2[CH:13]=[C:14]([S:17][CH3:18])[CH:15]=[CH:16][C:8]=2[O:7][C:6]2[CH:19]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[CH2:11]1
Reactant: CSc1ccc2c(c1)C(=O)Cc1ccc(C)cc1O2
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CSc1ccc2c(c1)C(Cl)Cc1ccc(C)cc1O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.5 G. of 10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin-10-one are dissolved in 75 ml. of benzene. 7.5 G. of anhydrous calcium chloride are added thereto and the mixture is saturated with hydrogen chloride. Then, the resulting mixture is stirred at room temperature for 16 hours and filtered. The filtrate is evaporated in vacuo and there is obtained 10-chloro-10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin.