Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]1([S:19]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a suspension of 6 (5.0 g, 22.2 mmol) in dichloromethane (130 mL) was added benzenesulfonyl chloride (4.25 mL, 33.3 mmol), tetra-n-butylammonium hydrogen sulphate (0.98 g, 2.98 mmol) and 50% aqueous NaOH (4.2 mL). The reaction mixture was stirred for 2 h then poured onto water (500 mL), extracted with dichloromethane (3×200 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (2×150 mL) and dried (MgSO4). Concentration produced a white solid which was washed with ether (3×150 mL) to give product 7 as a light orange solid (7.34 g, 91%); 1H NMR (400 MHz, CDCl3+4 drops d4-MeOH) δ 9.95 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.38 (s, 1H), 8.19 (m, 2H), 7.62 (tt, J=7.5, 1.3 Hz, 1H), 7.51 (t, J=7.1 Hz, 2H).
Reaction SMILES: [CH:1]1([CH:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])[CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[CH3:30]COCC>CO>[CH:1]1([CH:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])[CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:30])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC=CC(CNc1ccc(CCC(=O)O)cc1)C1CCCCC1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: CCCC=CC(CNc1ccc(CCC(=O)OC)cc1)C1CCCCC1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(2-cyclohexylhept-3-enylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(2-cyclohexylhept-3-enylamino)hydrocinnamate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[CH:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][CH2:43][C:44]1[CH:64]=[C:63]([Cl:65])[C:47]2[O:48][C:49]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:50][C:46]=2[C:45]=1[Cl:66]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][CH2:43][C:44]2[CH:64]=[C:63]([Cl:65])[C:47]3[O:48][C:49]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[O:50][C:46]=3[C:45]=2[Cl:66])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[CH:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4ncncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Nc1nc(/C(=N/OCc2cc(Cl)c3c(c2Cl)OC(c2ccccc2)(c2ccccc2)O3)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4ncncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.4 %

Procedure:
(6R, 7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (100 mg) (0.17 mmol) and 93 mg (0.22 mmol) of 5-[(aminooxy)methyl]-4,7-dichloro-2,2-diphenyl-1,3-benzodioxol hydrochloride are dissolved in 2 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours the solvent is distilled off in a high vacuum at room temperature. The residue is crystallized using diethyl ether. The product is filtered off under suction and washed with diethyl ether and water. There are obtained 160 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]imino]-acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder after drying in a high vacuum at room temperature.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:8])=[C:5]([Cl:7])[N:6]=1.O1CCOCC1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:2]2[S:3][C:4]([Br:8])=[C:5]([Cl:7])[N:6]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc(Br)sc1Br
Solvent: C1COCCO1
Product: COc1ccc(CNc2nc(Cl)c(Br)s2)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a 250 mL round-bottomed flask was added 2,5-dibromo-4-chlorothiazole (5.9 g, 21 mmol), p-dioxane (50 mL, 587 mmol), and 4-methoxybenzylamine (3 mL, 21 mmol). The solution was stirred at 75° C. for 4 hours. The reaction was cooled to room temperature, and the solvent was removed. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (1×25 mL), saturated sodium chloride (1×25 mL), water (1×25 mL), and dried over Na2SO4, filtered and concentrated in vacuum. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient (5%→50% EtOAc in hexane) to provide N-(4-methoxybenzyl)-5-bromo-4-chlorothiazol-2-amine (5.5 g, 80% yield), m/z (%): 334.1 (100%, M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:7]([C:6]1[S:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)[CH3:8]
Reactant: CCc1sc(C(=O)OC)cc1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (300 mg, 1.204 mmol), potassium carbonate (832 mg, 6.02 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (326 mg, 1.565 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (30.8 mg, 0.060 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (301 mg, 1.204 mmol, 100% yield) as a brown oil: LCMS (ES) m/e 251 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1cc(Cl)ccc1OCC(F)(F)F

Procedure:
Commercially available, methyl 5-chloro-2-hydroxybenzoate (Maybridge), potassium carbonate, 2,2,2-trifluoroethyl trifluoromethanesulfonate (TCI) and sodium hydroxide were processed according to the method of Example 130A to obtain the title compound. MS (ESI+) m/z 253 (M−H)'.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[N:10][OH:11])[CH3:9])[C:5]([C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[CH:4][N:3]=1>C(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[N+:10]([O-:11])=[C:8]2[CH3:9])=[CH:4][N:3]=1
Reactant: CC(=NO)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)cc1-c1cc2cnc(Cl)cc2c(C)[n+]1[O-]
Temperature: 60 °C
Yield: 57.8 %

Procedure:
A mixture of 1-(2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)pyridin-4-yl)ethanone oxime (700 mg, 2.0 mmol) and silver nitrate (−10 wt. % on silica gel, +230 mesh, 825 mg, 0.5 mmol) in chloroform (12 mL) was heated at 60° C. for 1 hour. The cooled reaction mixture was treated with silica gel (2 g), concentrated in vacuo, and purified by flash chromatography (silica, 12 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as pale yellow solid (350 mg, 50% over two steps), which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([OH:14])[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1sc2ccccc2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1-(3-phenylbenzo[b]thiophen-2-yl)ethanone (430 mg, 1.704 mmol) dissolved in MeOH (5 mL) at rt was added sodium borohydride (0.093 mL, 2.64 mmol). After 5 min, no starting material remained. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine then stirred over MgSO4, filtered, and concentrated under reduced pressure to give 1-(3-phenylbenzo[b]thiophen-2-yl)ethanol as a colorless, crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.46 (d, J=6.3 Hz, 3H), 2.19 (br. s., 1H), 5.09 (q, J=6.5 Hz, 1H), 7.16-7.40 (m, 8H), 7.70-7.77 (m, 1H).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(N(C)C)=C(C)C.[F:15][C:16]([F:32])([F:31])[CH2:17][N:18]1[CH:22]=[C:21]([NH:23][C:24]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25]2)[CH:20]=[N:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([C:24]1([N:23]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][C:16]([F:31])([F:15])[F:32])[CH:22]=2)[C:1](=[O:6])[CH:2]=[C:3]=[CH2:4])[CH2:28][CH2:27][O:26][CH2:25]1)#[N:30]
Reactant: N#CC1(Nc2cnn(CC(F)(F)F)c2)CCOC1
Reactant: CC#CC(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C=CC(=O)N(c1cnn(CC(F)(F)F)c1)C1(C#N)CCOC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
As shown in step 24-ii of Scheme 24, to a solution of but-2-ynoic acid (833.6 mg, 9.915 mmol) in DCM (12 mL) at 0° C. was added 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (1.325 g, 1.312 mL, 9.915 mmol). After stirring for 40 minutes, the reaction mixture was cooled to −78° C. and a solution of 3-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]tetrahydrofuran-3-carbonitrile (Compound 2075, 1.72 g, 6.610 mmol) and DIEA (2.563 g, 3.454 mL, 19.83 mmol) in DCM (12 mL) was added. The reaction mixture was warmed to 0° C. (ice-water bath), and after 1 hour the mixture was warmed to 23° C. After 30 min at 23° C., the reaction mixture was partitioned between water and EtOAc (100 mL each). The organics were separated (insoluble precipitate is present), washed with water then brine (100 mL each), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (0-80% EtOAc/hexanes) to provide N-(3-cyanotetrahydrofuran-3-yl)-N-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]buta-2,3-dienamide (Compound 2076, 1.48 g) as a yellow oil: ESMS (M+H) 327.20; 1H NMR (CDCl3, 300 MHz) δ 7.70 (s, 1H), 7.63 (s, 1H), 5.57 (t, J=6, 1H), 5.19 (d, J=6, 2H), 4.77 (q, J=9, 2H), 4.00 (m, 4H), 2.50 (m, 1H), 2.30 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:34][CH2:35][C:36]3[N:37]=[C:38]([C:42]4[O:43][CH:44]=[CH:45][CH:46]=4)[O:39][C:40]=3[CH3:41])=[C:28]([CH:33]=2)[C:29]([O:31]C)=[O:30])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:34][CH2:35][C:36]3[N:37]=[C:38]([C:42]4[O:43][CH:44]=[CH:45][CH:46]=4)[O:39][C:40]=3[CH3:41])=[C:28]([CH:33]=2)[C:29]([OH:31])=[O:30])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C(=O)OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C(=O)O)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of methyl 5-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (1 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration to give 5-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoic acid as colorless crystals (0.29 g, yield 74%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 169-170° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([NH2:22])=[N:16][C:15]=3[NH:14][CH:13]=2)=[CH:6][CH:5]=1.CO.O1CCCC1.Cl>[OH-].[Na+]>[NH2:22][C:17]1[NH:18][C:19](=[O:21])[C:20]2[C:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][CH:6]=3)=[CH:13][NH:14][C:15]=2[N:16]=1
Reactant: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A mixture of 3.17 g (10.15 mmol) of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl]benzoic acid methyl ester, prepared in Example 3, in 30 ml of 1N aqueous sodium hydroxide and 5 ml methanol was stirred for 20 hours at room temperature. Tetrahydrofuran (5 ml) was added and the mixture was stirred for 4 hours then neutralized with 30 ml of 1N aqueous hydrochloric acid. The resulting precipitate was separated by filtration, washed with water (20 ml) and dried in a vacuum oven at 50° C. to obtain 2.65 g of the above product in a yield of 87 percent. 1H NMR (DMSO-d6) δ2.45 (m, 2H), 2.91 (m, 2H), 5.99 (s, 2H), 6.27 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 10.14 (s, 1H), 10.59 (d, J=2.0 Hz, 1H), 13.2 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][OH:18])[C:10]=3[OH:19])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:18][CH2:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: -5 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.98 g (13.0 mmol) 2-(5-chloro-2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol in 60 ml anhydrous THF. Triethylamine (6.4 ml) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (1.62 g, 15.5 mmol) was added dropwise and the mixture was stirred for 1 hr at −10-0° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with 100 ml diethyl ether. The organic layer was washed with 1 N HCl and water, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to yield a yellow oil which was recrystallized in ethanol to give 1.73 g (34%) of a light yellow solid. 1H NMR (CDCl3) delta: 11.00 (s, 1H, Ar—OH), 7.92 (s, 1H, Ar—H benzotriazole), 7.88 (s, 1H, Ar—H phenol), 7.87 (d, 1H, Ar—H benzotriazole), 7.45 (d, 1H, Ar—H benzotriazole), 7.06 (s, 1H, Ar—H phenol), 6.21 (s, 1H, C═C—H trans), 5.62 (s, 1H, C═C—H cis), 5.38 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C-:35]#[N:36].[K+]>O>[Cl:23][C:21]1[CH:20]=[CH:19][C:12]2[CH2:13][CH2:14][CH:15]3[C:10]([C:11]=2[CH:22]=1)=[N:9][N:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]#[N:36])=[CH:3][CH:4]=1)[C:17](=[O:18])[CH2:16]3
Reactant: Nc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1
Reaction time: 8 h

Procedure:
2-(4-Aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one is added to the mixture of water and concentrated hydrochloric acid which is cooled on an ice bath and then an aqueous solution of sodium nitrite is added dropwise. The mixture is stirred under ice-cooling for 30 minutes and then neutralized with sodium carbonate. The solution is added dropwise with stirring to a solution of cuprous cyanide and potassium cyanide which is previously prepared. The mixture is stirred under ice-cooling for 30 minutes and allowed to stand overnight at room temperature. The precipitated crystals are collected by filtration to give 9-chloro-2-(4-cyanophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[CH:4][C:5]([Cl:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Br:12][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH:8]([O:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:9])=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1cc(N)c(Br)cc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(N)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
To a solution of 1-(5-amino-4-bromo-2-chloro-phenyl)-ethanol (0.195 g, 0.778 mmol) in DMF (3 ml) was added tert-butyl-dimethylsilyl chloride (0.152 g, 1.011 mmol) and imidazole (0.069 g, 1.011 mmol). The mixture was stirred at room temperature for six hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 2-bromo-5-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-chloro-phenylamine (0.262 g, 92%) as a clear oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][O:23][CH2:24]Cl.O>C1COCC1>[CH3:22][O:23][CH2:24][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19]
Reactant: COCCl
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -30 °C

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) was added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. methoxymethylchloride (1.14 ml) was added. The RM was then allowed to warm to −30° C. over 3 h and water was added. The aqueous layer was extracted with DCM, the combined organic layers evaporated and the residue was then purified by normal phase chromatography, eluting with DCM, to give the title compound as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Product: Clc1ccc(C2=CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 139.5 %

Procedure:
HCl (conc., 1.5 mL) was slowly added to a flask containing tert-butyl 4-(3,4-dichlorophenyl)-4-hydroxypiperidine-1-carboxylate (200 mg, 0.58 mmol). The mixture was stirred at rt for 30 mins, heated to 90° C. for 5 h and then cooled overnight. The resulting precipitate was collected by filtration to give 4-(3,4-dichlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (107 mg, 70% yield). MS found: 215.6 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: O=C(O)CCCc1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCc2c(F)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-bromo-2-fluoro-phenyl)-butyric acid (0.625 g, 2.154 mmol) and DMF (0.0084 g, 0.108 mmol) in dichloromethane (10 mL) is added oxalyl chloride (0.558 g, 4.309 mmol). The mixture is stirred for 30 min and concentrated in vacuo at room temperature to give a yellow oil, which is re-dissolved in dichloromethane (20 mL) and added dropwise to aluminum chloride (0.402 g, 3.016 mmol) in dichloromethane (20 mL). The mixture is refluxed for 3.5 hours, and then poured into ice-water. The resulting mixture is extracted twice with diethyl ether. The organic phases are combined, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered through a cotton plug, and concentrated. The resulting residue is purified by silica gel flash chromatography (hexanes-ethyl acetate, 19:1 to 9:1) to afford 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-one; 1H NMR (400 MHz, CDCl3) δ ppm 2.13-2.19 (m, 2 H), 2.67 (t, J=6.6 Hz, 2 H), 2.90 (t, J=6.2 Hz, 2 H), 7.40 (dd, J=8.5, 1.9 Hz, 1 H), 7.98 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[CH3:9])[N:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[O:16][CH3:17].[OH-].[Na+].Cl>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[CH3:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1nc(C(C)(F)F)cc(N)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(N)cc(C(C)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of methyl 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (0.229 g, 0.930 mmol) in THF (2.325 ml) and MeOH (2.325 ml) was added a 2 N solution of sodium hydroxide (1.395 ml, 2.79 mmol). The reaction mixture was stirred at room temperature (LC monitoring). After 4 h, the reaction mixture was acidified with a 2 N solution of HCl (2 mL) and then concentrated (rotavap). The resulting white solid was dissolved into DMF and a few drops of water and was purified by preparative HPLC (reverse phase, C18 column) to afford 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinic acid (188 mg, 0.810 mmol, 87% yield) as an orange oil. EIMS m/z 208; 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 6.71 (dd, J=17.6, 10.9 Hz, 1H), 5.98 (dd, J=17.6, 1.0 Hz, 1H), 5.42 (dd, J=10.9, 1.0 Hz, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.94, 152.06, 148.02, 143.34, 141.60, 136.73, 118.02, 108.63, 61.49, 52.84.