Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.Cl[C:34]1[CH:39]=[C:38]([N:40]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:37]2[N:57]=[CH:58][C:59]([C:60]3[CH:61]=[N:62][C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:64][CH:65]=3)=[C:36]2[N:35]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:54][Si:53]([CH3:56])([CH3:55])[CH2:52][CH2:51][O:50][CH2:49][N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:38]1[N:37]2[N:57]=[CH:58][C:59]([C:60]3[CH:61]=[N:62][C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:64][CH:65]=3)=[C:36]2[N:35]=[C:34]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:39]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)cc(-c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)n2C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-ylboronic acid (0.24 mmol, 70 mg), K3PO4 (0.36 mmol, 77 mg), and PdCl2(dppf).CH2Cl2 (0.012 mmol, 9.8 mg) were added to a solution of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.12 mmol, 72 mg) in dioxane (4 mL) and H2O (0.5 mL). The resulting solution was stirred at 90° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 2-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5-methoxy-1H-indole-1-carboxylate, LCMS tR=3.48 Min (5 min run, UV254nm). Mass calculated for, M+ 792.3, observed LC/MS m/z 793.2 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])[O:6][CH:7]=1.C([O-])(=[O:23])C.[Na+]>C(O)(=O)C>[F:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:5]1[O:6][CH:7]=[C:3]([CH2:2][OH:23])[N:4]=1
Reactant: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Temperature: 25 °C

Procedure:
A solution of 4-chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole (1.000 g, 3.27 mmol) and sodium acetate (0.536 g, 6.54 mmol) in acetic acid (10 ml) is refluxed for 55 h. The reaction mixture is cooled to r.t., concentrated in vacuo and the resulting residue is dissolved in ethanol (5 ml) and 7M potassium hydroxide (KOH) (12 ml). The solution is refluxed for 5 h and cooled to r.t. Saturated ammonium chloride (NH4Cl) is added and the mixture is extracted with ethyl acetate (3×). The extract is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:1) yielding {2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol as a colorless solid. Yield 0.791 g (84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si](C(C)C)(C(C)C)C(C)C)[C:14]=3[O:30][CH3:31])[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:62][C:63]([O:65][CH3:66])=[O:64]>>[CH3:66][O:65][C:63](=[O:64])[CH2:62][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]2[N:10]([C:32](=[O:33])[C:34]3[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=3[F:40])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:12]2)[C:14]=1[O:30][CH3:31]
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reactant: COC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1OC
Reaction time: 12 h

Procedure:
[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (3.31 mmol), prepared as described in example 4, is treated with tetrabutylammonium fluoride (1 M in THF) (4.97 mmol) at room temperature for 40 minutes. Methyl bromoacetate (4.97 mmol) is then added. After 12 hours, the reaction is complete as determined by LC/MS. Purification is accomplished by silica flash chromatography (25% EtOAc/hexane) to give {3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 3H), 7.04 (m, 3H), 6.95 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.82 (dd, J1=8 Hz, J2=1.6 Hz), 6.76 (m, 2H), 4.7 (s, 2H), 4.1 (s, 3H); LC/MS (ES+): 505.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[C:20]([O:30][CH3:31])[CH:19]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:15]=[CH:14][N:13]([C:18]3[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([OH:26])([CH3:27])[CH3:25])=[C:20]([O:30][CH3:31])[CH:19]=3)[C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(CSc2ccc(Cl)cc2)nc[nH]1
Reactant: COc1cc(Br)ccc1OCC(C)(C)O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-n2cnc(CSc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 110 °C
Reaction time: 1 h
Yield: 3.01 %

Procedure:
A mixture of 6-((4-chlorophenylthio)methyl)pyrimidin-4(3H)-one Part B (25 mg, 0.10 mmol), 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol Part B of Procedure 1 (32.7 mg, 0.12 mmol), N1,N2-dimethylethane-1,2-diamine (26.2 mg, 0.30 mmol), potassium phosphate tribasic (63.0 mg, 0.30 mmol) and copper (I) iodide (18.84 mg, 0.10 mmol) in dioxane (4.0 mL) was stirred in a sealed tube at 110° C. for 60 min. After the mixture had cooled to RT, the precipitate removed by filtration and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel/CH2Cl2-10% MeOH/CH2Cl2 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product). The pure fractions were lyophilized with MeCN/H2O (1:1, 4 mL) to afford the title compound 6-((4-chlorophenylthio)methyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one G-1 as an off-white solid (1.40 mg, 3.01% yield). LC/MS 447 (M+H)+, tR 0.92 min (method 5); 1H NMR (500 MHz, Chloroform-D) δ ppm 8.14 (1H, br. s.), 7.27-7.36 (4H, m), 6.99 (1H, d, J=8.25 Hz), 6.79-6.88 (2H, m), 6.45 (1H, s), 3.96 (2H, s), 3.82-3.90 (5H, m), 1.36 (6H, s).
Reaction SMILES: O[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH3:24]>OS(C(F)(F)F)(=O)=O>[Br:14][C:15]1[C:16]([CH3:24])=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][C:20]=1[CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])cc(CN2C(=O)c3ccccc3C2=O)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
N-(Hydroxymethyl)phtalimide (2.36 g, 13.3 mmol) was dissolved in 20 mL of triflic acid at 0° C. The mixture was stirred for 20 minutes and then 2-bromo-5-nitrotoluene (2.88 g, 1 eq) was added. This solution was allowed to warm to room temperature and was stirred for 18 h. The mixture was poured slowly into 300 mL of ice-cold water. The aqueous layer was extracted with DCM. The combined organic layers were washed with 100 mL of water, dried over Na2SO4, filtered and evaporated to yield expected compound as a white solid (4.71 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:3]2[C:4]3[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:26][CH:25]=1)([OH:29])=[O:28]
Reactant: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1

Procedure:
Combine 7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.16 mmol), potassium carbonate (0.87 g, 6.3 mmol), methanol (2 mL), water (2 mL) and heat at 50° C. for 3 h. Purify by SCX chromatography to obtain 6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[CH:9]=3.CCN(CC)CC.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>O1CCOCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[CH:9]=3
Reactant: NCc1ccccn1
Reactant: Cc1cc2nc(Cl)c3ccc(Br)cc3c2c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc2nc(NCc3ccccn3)c3ccc(Br)cc3c2c(Cl)n1
Temperature: 120 °C

Procedure:
To a solution of 9-bromo-1,6-dichloro-3-methyl-benzo[c][1,6]naphthyridine (0.12 g, 0.35 mMol) in anhydrous dioxane (4 mL) was added anhydrous Et3N (0.07 mL, 0.53 mMol), followed by 2-aminomethylpyridine (0.038 g, 0.35 mMol). The resulting reaction mixture was heated in a sealed tube at 120° C. for 5 hours. The reaction mixture was concentrated to a crude solid that was redissolved in EtOAc (10 mL). The EtOAc layer was washed with water (2×5 mL), brine (1×10 mL) and dried over MgSO4. The filtrate was concentrated and the resulting residue was purified by flash chromatography using an EtOAc/Hexanes gradient to afford 9-bromo-1-chloro-3-methyl-N-(pyridin-2-ylmethyl)benzo[c]-1,6-naphthyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) 9.88 (d, 1H), 8.65 (bs, 1H), 7.97 (d, 1H), 7.83-7.80 (dd, 1H), 7.75 (t, 1H), 7.64 (bs, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 4.99 (d, 2H), 2.62 (s, 3H). LRMS calculated for C19H14BrClN4 [M+H]+, 415.0; found 415.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:22]([N:9]1[C:10]2[C@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2F)n1Cc1ccccc1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A solution of (4R,7S)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 38; 890 mg, 3.11 mmol), terabutylammonium iodide (860 mg, 2.33 mmol) and benzyl bromide (1.7 mL, 14.3 mmol) in dimethylformamide (15 mL) was heated in an oil-bath at 100° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. Dichloromethane (100 μL) was added and the solution was washed with water (5×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL), dried (magnesium sulfate, filtered, and evaporated. The residue was purified using an ISCO 120 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions containing the product were concentrated and then co-evaporated with ether. Petroleum ether was added and the mixture was scratched to give a solid. The solvent was evaporated and the residue was co-evaporated three times with ethanol, and then dried under high vacuum at 65° C. and then at 75° C. to give (4R,7S)-1-benzyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (462 mg, 39%) as a pale yellow solid. ES(+)-MS (M+H) 377.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC1=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Reaction time: 35 h
Yield: 8.1 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 546 mg of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 2-(3), and 200 mg of Lipase B was added thereto, followed by stirring at room temeprature for 35 hours. Any insoluble matter was removed by filtration and washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by short silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 35 mg (yield: 83%) of (S)-1,4-dihydro 2,6-dimethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([CH:35]1[CH2:37][CH2:36]1)[NH2:34]>>[CH:35]1([C:33]2[N:34]=[C:28]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:30][N:32]=2)[CH2:37][CH2:36]1
Reactant: NC(=NO)C1CC1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)CC1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 30 mg (0.306 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 312 mg (41% of theory)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14]([Cl:25])=[CH:15][C:16]2[O:21][CH2:20][CH2:19][C:18](=[N:22][OH:23])[C:17]=2[CH:24]=1>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([Cl:25])=[CH:15][C:16]2[O:21][CH2:20][CH2:19][C:18](=[N:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:17]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCOc2cc(Cl)c(Cl)cc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCOc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of p-toluenesulfonyl chloride (103 g) in 125 ml pyridine was added dropwise at 5°-10° to 6,7-dichloro-2,3-dihydro-4-(hydroxyimino)-4H-1-benzopyran (62.5 g) in 250 ml pyridine. The reaction mixture was then stirred for 20 hours at room temperature, poured into ice-water to separate out the title compound, which was filtered, washed several times with water, then once with ether, and finally dried in air. Yield: 101.8 g; m.p. 180°-184°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[C:2]([NH2:1])[N:3]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The title compound was prepared from (2-amino-6-chloropyridin-3-yl)-(5-fluoro-2-methoxyphenyl)methanone (Example 19) and 4-amino-1-N-Bocpiperidine (Astatech, >96%) using the procedure described in Step B. Example 6. HRMS, observed: 445.2252, Calcd for (M+H)+: 445.2246.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[N:8]=C[N:6]3[CH:11]=[N:12][N:13]=[C:5]3[C:4]=2[CH:3]=1>CO.C(Cl)Cl>[Cl:1][C:2]1[S:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][CH:11]=[N:12][N:13]=2)[CH:3]=1
Reactant: Clc1cc2c(ncn3cnnc23)s1
Solvent: ClCCl
Solvent: CO
Product: Nc1sc(Cl)cc1-c1nnc[nH]1
Temperature: 60 °C

Procedure:
To a stirring mixture of 8-chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (60 mg, 0.285 mmol) in MeOH (10 mL) was added N-methylethyl 1,2-diamine (106 mg, 1.4 mmol). The resulting mixture was warmed to 60° C. for 1 hr. The reaction mixture was cooled to rt and then diluted with DCM. This mixture was then washed several times with a saturated NH4Cl solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine. This amine was taken directly to the next coupling reaction without further purification. Retention time (min)=1.227, method [1], MS (ESI) 201.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH2:7][C:8]#[N:9])[CH3:2].N>[Ni].C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][NH2:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(CC#N)cc1OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOc1ccc(CCN)cc1OCC

Procedure:
100 kg. of 3,4-diethoxy-benzyl cyanide are hydrogenated in 310 1. of a 80 to 96% aqueous ethanol containing 9 to 12% of ammonia in the presence of 24 kg. of a Raney-nickel catalyst pretreated according to Example 3, at 45° to 68° C under a hydrogen overpressure of 8 to 10 atm. The catalyst is filtered off, the solution is evaporated and the residue is subjected to fractionation in vacuo. Thus 96 kg. of highly pure 3,4-diethoxy-beta-phenyl-ethylamine are obtained. The purity is almost 100%. The mono-desethylated beta-phenyl-ethylamine derivative is present at most in traces in such a small amount, which can not be detected by thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: NCCc1cccnc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a stirring solution of terephthalic acid monomethyl ester (500 mg, 2.5 mmol) and oxalyl chloride (0.44 mL, 5.03 mmol) in dichloromethane (20 mL), is added 3 drops of dimethylformamide and the reaction is stirred for 2 h at room temperature. The reaction is concentrated in vacuo and then redissolved in dichloromethane. The solution is slowly added to a stirring solution of 3-(2-aminoethyl)pyridine (308 mg, 2.52 mmol) and n-methylmorpholine (0.28 mL, 2.52 mmol) in dichloromethane (20 mL). After 20 min, the reaction is washed with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane. The organic portion is dried with sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with methanol and dichloromethane to obtain 613 mg (86%) of the title compound. MS (ES+) m/e 285.1 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH2:21][CH:22]([F:24])[F:23])[C:14]=2[F:25])[N:6]=1)=[O:4].Cl>CO.[OH-].[Na+]>[NH2:12][C:9]1[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH2:21][CH:22]([F:24])[F:23])[C:14]=2[F:25])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[Cl:11]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OCC(F)F)c2F)cc(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(-c2ccc(Cl)c(OCC(F)F)c2F)nc(C(=O)O)c1Cl
Yield: 87.5 %

Procedure:
A solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(2,2-difluroethoxy)phenyl)pyridine-2-carboxylic acid methyl ester (0.300 g, 0.0008 mol) in methanol (5 mL) and sodium hydroxide (1N, 2 mL) was heated to reflux 1 hour and then acidified to pH 3 (concentrated hydrochloric acid) and allowed to cool. The resulting solid was collected and dried to give 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(2,2-difluoroethoxy)phenyl)pyridine-2-carboxylic acid (0.270 g, 0.0007 mol): mp 183-184° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:22]([OH:24])=[O:23]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:24])=[O:23])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: OC(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)C(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 6 %

Procedure:
Compound 12 (600 mg, 2.16 mmol) was dissolved in a 25:1 mixture of concentrated sulfuric acid:formic acid (19.76 mL) and left without stirring for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified via prep-HPLC (ISCO) in silica gel column with a gradient of ethyl acetate (20-80%) in hexanes to afford compound 13 as an orange oil (40 mg, 6%). 1H NMR (DMSO-d6) δ (ppm): 7.68-7.64 (m, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.40-7.21 (m, 9H), 5.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27](O)[CH2:28][OH:29]>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:27][CH2:28][OH:29])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: OCCO
Product: C/C(=C\c1ccc(C(=O)OCCO)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and ethyleneglycol there can be obtained 2-hydroxyethyl p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoate of melting point 138°-139° C.