Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([C:23]([F:26])([F:25])[F:24])/[CH:3]=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2([CH3:22])OCC[O:18]2)[CH:12]=1)=[O:6].Cl>CC(C)=O.O>[C:17]([C:13]1[CH:12]=[C:11]([NH:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:1])([F:27])[C:23]([F:26])([F:24])[F:25])[CH:16]=[CH:15][N:14]=1)(=[O:18])[CH3:22]
Reactant: CC1(c2cc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)ccn2)OCCO1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)ccn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,5,5,5-Pentafluoro-N-[2-[[2-(2-methyl-1,3-dioxolan-2-yl)-4-pyridyl]amino]ethyl]pent-2-enamide (35 mg, 0.09 mmol) was dissolved in aceton (1 ml), 4M hydrochloric acid (0.5 ml) was added and the mixture was stirred in a closed vessel at 100° C. for 15 minutes with microwave heating. The mixture was diluted with water, extracted with ethyl acetate and the organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 2.5 mg (0.0071 mmol, 7.9%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2cnc(Br)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1

Procedure:
The title compound (0.303 g, 61%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.28 g, 1.37 mmol), 1-methylethyl 4-{[(5-bromo-2-pyrazinyl)oxy]methyl}-1-piperidinecarboxylate (crude material prepared in Step 2), Pd(PPh3)2Cl2 (82 mg, 0.11 mmol), 2M Na2CO3 (8 mL) and DME (8 mL) in a manner similar to Example 21, Step 3. The crude material was purified by flash chromatography on a silica gel column eluted with 1:20 acetone/CH2Cl2 to 1:10 acetone/CH2Cl2 followed by trituration with hot hexanes containing 1% MeOH to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 8.31 (s, 1H), 8.12 (d, 2H, J=8.3 Hz), 8.03 (d, 2H, J=8.3 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 4H), 3.09 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 434 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Br[C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[NH:39][CH:40]=[CH:41][C:34]=12.C(=O)(O)[O-].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:39][CH:40]=[CH:41][C:34]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: Brc1ccnc2[nH]ccc12
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.28 g, 0.66 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (0.14 g, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol) and sodium bicarbonate (0.28 g, 3.3 mmol) in a solution of water (0.5 mL) and 1,4-dioxane (1 mL) was degassed for a while and sealed. The mixture was stirred at 85° C. for 3 h. After cooling the mixture was diluted with ethyl acetate. The organic solution was washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.15 g). LCMS (M+H)+: m/z=415.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([Br:13])=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:13][C:9]1[C:10]([F:12])=[CH:11][C:2]2[NH:1][N:15]=[CH:14][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(C)c(N)cc(F)c1Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(Br)c(F)cc2[nH]ncc12
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-5-fluoro-2-methylbenzoate (1.33 g, 5.09 mmol) in acetic acid (25 mL) heated to 50° C. was added a solution of sodium nitrite (369 mg, 5.34 mmol) in water (1 mL), and the mixture was stirred for 1.5 hr and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (700 mg, yield 52%).
Reaction SMILES: C[CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64][O:65][C:66](=[O:78])[CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[Li+].[OH-]>C1COCC1>[C:74]([O:73][C:71]([NH:70][CH2:69][CH2:68][CH2:67][C:66]([O:65][CH2:64][O:63][C@@H:14]1[CH2:15][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH2:19][C@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]3[CH:39]=[CH:38][C:37]([C@H:40]4[CH2:57][C@@:55]5([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]5([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]5[C:41]4=[C:42]4[C:47]([CH2:48][CH2:49]5)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]4)=[CH:36][CH:35]=3)[CH3:33])[CH2:17]2)[C@@H:23]2[C@@H:13]1[C@H:12]1[C@:26]([CH3:27])([C@@H:25]([OH:28])[CH2:24]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:11]1)=[O:78])=[O:72])([CH3:77])([CH3:75])[CH3:76]
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCOC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCOC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]45)cc3)C[C@@]21C

Procedure:
The compound of Example 11B is dissolved in THF; an aqueous solution of LiOH is added, and the resultant mixture is stirred at ambient temperature for 3 hours. The reaction is quenched by addition of aqueous phosphoric acid (1N), and extracted with ethyl acetate. The crude material is carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[CH:12]=[N:11]2)=[CH:4][C:5]=1[O:9][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(-n2ncc(=O)n(C)c2=O)c(Cl)cc1Cl
Yield: 75.7 %

Procedure:
In a manner similar to Example II, Step C, the reaction of 0.86 g (0.0030 mole) of 2-(2,4-dichloro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 9, Example III H) with 0.62 g (0.0045 mole) of potassium carbonate and 0.75 g (0.0045 mole) of ethyl bromoacetate in 10 mL of acetone produced an oil. The oil crystallized upon treatment with heptane to yield 0.85 g of ethyl 2,4-dichloro-5-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-2-yl]phenoxyacetate (mp 115°-117° C.), Compound 22 in the tables.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CC(O)=O>ClC(Cl)C>[CH3:4][O:3][C:1]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:15]/[NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-carbomethoxy benzaldehyde (5.0 g, 36.46 mmol) in dichloroethane (40 mL) was added tert-butyl carbazate (4.03 g, 30.46 mmol) followed by AcOH (1.74 mL, 30.46 mmol). After 1.5 hours, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This material was used without any further purification in the next step. 1H NMR (CDCl3, 500 MHz): 8.03 (d, J=8.5 Hz, 3H), 7.93 (bs, 1H), 7.8 (d, J=8.2 Hz, 2H), 3.96 (s, 3H), 1.58 (s, 9H). LC-MS=3.1; (M+H−56)=223.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>CC(C)=O>[Cl:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Add 4-aminobenzonitrile (3.125 g, 26.4 mmol) and potassium carbonate (8.04 g, 58.2 mmol) to a solution of 4-chloromethyl-benzoyl chloride (5.00 g, 26.4 mmol) in acetone (60 mL). Heat at reflux for 4 hours. Cool to room temperature, filter, and concentrate to afford the title compound as a yellow solid (7.30 g, 91%): 1H NMR (DMSO-d6) δ 4.86 (s, 2H), 7.61 (d, 2H), 7.83 (d, 2H), 7.94-8.03 (m, 4H), 10.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Cl:17]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.36 mmol) and N-chlorosuccinimide (182 mg, 1.36 mmol) in tetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (3.4 ml, 20.4 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (275 mg, 1.14 mmol, 84% yield) as a orange oil: LCMS (ES) m/e 241, 243 (M, M+2)+.
Reaction SMILES: [C:1](#[N:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.S(=O)(=O)(O)O.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]#[N:10])=[CH:19][CH:18]=1
Reactant: N#CC(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: O=S(=O)(O)O
Product: N#CC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To a mixture of mandelonitrile (5 g) and chlorobenzene (15.7 g) was added sulfuric acid (9.8 ml) dropwise while the temperature of the mixture was maintained at 5°-10° C. After completion of dropwise addition, the mixture was stirred for another 1.5 hours. This reaction mixture was poured in ice-water and the syrup that had separated out was extracted into ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (3.6 g) as pale yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30](=[O:41])[N:29]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH:28]=1>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[C:30](=[O:41])[N:29]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH:28]=1
Reactant: COc1ccc(Cn2cc(Cl)c3ccc(S(=O)(=O)Cl)cc3c2=O)cc1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)cn(Cc4ccc(OC)cc4)c(=O)c3c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (0.213 g, 0.967 mmol) and THF (4.40 mL), and the vessel was cooled to −78° C. for 15 minutes. LHMDS (1.0 M in THF) (1.055 mL, 1.055 mmol) was then added drop wise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 4-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-7-sulfonyl chloride (0.350 g, 0.879 mmol) in THF (1.60 mL) was added drop wise. The bath was removed, and the resulting mixture was stirred for 45 minutes, until complete conversion to 4-chloro-N,2-bis(4-methoxybenzyl)-1-oxo-N-(thiazol-2-yl)-1,2-dihydroisoquinoline-7-sulfonamide. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel chromatography (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes to provide 0.250 g of 4-chloro-N,2-bis(4-methoxybenzyl)-1-oxo-N-(thiazol-2-yl)-1,2-dihydroisoquinoline-7-sulfonamide. m/z (ESI) 583.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17]([C:19]1[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=1)=[O:18])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccc(F)cc2C1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
The mixture of 5-fluoro-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (86) (190 mg, 0.50 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (87) as a pale brown solid (178 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19]C(=O)OC(C)(C)C)[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH2:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1

Procedure:
(R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (5.05 g, 10.7 mmol) was treated with TFA (10 mL) in CH2Cl2 (30 ml). Once the reaction was complete, the reaction was concentrated in vacuo and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organics were separated, then washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated under reduced pressure to give (R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine which was directly used for the next step without further purification (2.55 g, 64%). LC/MS (uplc) MH+ 375.1, 0.83 min.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[C:29]1([CH2:39][O:40][NH2:41])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[C:29]1([CH2:39][O:40][NH:41][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: NOCc1cccc2ccccc12
Solvent: CN(C)C=O
Product: O=C(NOCc1cccc2ccccc12)c1ccccc1NCc1ccncc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C, 150 mg) and O-naphthalen-1-ylmethyl-hydroxylamine (preparation 53, 1.05 eq.) was dissolved in DMF and the stirred mixture was heated to 50° C. The reaction mixture was stirred at this temperature for 15 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) and gave the title compound. 13C-NMR (DMSO-d6) δ 167.3, 149.5, 149.1, 148.4, 133.2, 132.5, 131.9, 131.4, 129.3, 128.4, 128.2, 126.3, 126.1, 125.9, 125.2, 124.8, 121.9, 114.8, 113.4, 111.5, 75.3, 44.8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([C:8]([C:7]3[CH:11]=[C:3]([CH:4]=[CH:5][C:6]=3[O:12][CH:13]([CH3:15])[CH3:14])[C:1]#[N:2])=[O:10])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CC=C(c2ccc(Cl)cc2)CC1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 5-cyano-2-isopropoxy-benzoic acid (CAS: 845616-14-0) and 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (commercial). MS (m/e): 381.1 (MH+, 100%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:29][C@H:30]([C:32]([OH:34])=[O:33])[CH3:31]>>[F:28][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([O:26][CH3:27])[CH:23]=1)[O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:29][C@@H:30]([CH3:31])[C:32]([OH:34])=[O:33])=[O:7])[N:9]=[CH:10]2)=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)c1ncc2cc(Oc3cc(F)cc(OC)c3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Product: COc1cc(F)cc(Oc2ccc3c(O)c(C(=O)N[C@@H](C)C(=O)O)ncc3c2)c1

Procedure:
Prepared in analogy to Example A-50 by reacting 7-(3-fluoro-5-methoxy-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (compound of example A-73 a) with L-alanine in a pressure tube for 3 days at 90 C. MS-(−)-ion M−1=399.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][C:43]#[N:44]>>[C:43]([CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)#[N:44]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: N#CCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCC#N)cc3)cc21

Procedure:
Analogously to Method I, 0.615 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.176 ml of 4-bromobutyronitrile are reacted. The title compound is obtained as a yellowish oil. Rf=0.16 (2:1 EtOAc-heptane); Rt=5.00.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.