Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][C:25]([NH:27]C(=O)OC(C)(C)C)=[N:24][CH:23]=2)[C:19]2[C:35](=[O:49])[N:36](CC3C=CC(OC)=CC=3OC)[CH2:37][C:18]=2[C:17]=1[F:50])=O)(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][C:25]([NH2:27])=[N:24][CH:23]=2)[C:19]2[C:35](=[O:49])[NH:36][CH2:37][C:18]=2[C:17]=1[F:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnc(NC(=O)OC(C)(C)C)s4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)s1

Procedure:
A solution of tert-butyl (5-(6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclo-hexyl)amino)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,3-thiazol-2-yl)carbamate (41.5 mg, 0.058 mmol) in TFA (5 mL) was heated to 65° C. for 3 h. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (10-20% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound as a TFA salt (6.7 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-2.11 (m, 9H), 3.73 (br s, 2H), 4.19 (d, J=3.79 Hz, 1H), 4.41 (d, J=3.03 Hz, 2H), 6.95 (d, J=3.03 Hz, 1H), 7.77 (br s, 2H), 8.44 (s, 1H), 8.93 (s, 1H). [M+H] calc'd for C16H19FN6OS, 363. found, 363.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([S:8]([C:11]1[CH:40]=[CH:39][C:14]([O:15][C:16]2[C:17]([CH:31]([O:34][Si](C)(C)C)[C:32]#[N:33])=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[NH:21][C:20]=3[CH:30]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]>>[CH2:6]([S:8]([C:11]1[CH:40]=[CH:39][C:14]([O:15][C:16]2[C:17]([CH:31]([OH:34])[C:32]([NH2:33])=[O:2])=[CH:18][C:19]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[NH:21][C:20]=3[CH:30]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(C#N)O[Si](C)(C)C)cc1
Reactant: O=S(=O)(O)O
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
80% sulfuric acid (0.2 ml) was added to (6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)((trimethylsilyl(oxy)acetonitrile (25 mg) obtained in Example 31 (step 1), and the reaction liquid was stirred at room temperature for 3 hours. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[S:16][CH:15]=2)[N:11]([CH3:29])[N:10]=1.[Cl:30]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[S:16][C:15]=2[Cl:30])[N:11]([CH3:29])[N:10]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1csc(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2cccc(C(F)(F)F)c2)sc1Cl
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-[5-(3-trifluoromethylphenyl)thien-3-yl]-1H-1,2,4-triazole (0.45 g, 1 mmol) and N-chlorosuccinimide (0.15 g, 1.1 mmol) in methylene chloride/glacial acetic acid (1:1, 2 mL) was refluxed under nitrogen for 2 days, cooled to room temperature, poured into water (10 mL) and extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (3×30 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (30 mL), dried over magnesium sulphate and chromatographed on silica to afford the product as a white solid (0.37 g, 76%): mp 53-54° C.; 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.71 (d, 2H), 7.60 (d, 1H), 7.54 (t, 1H), 7.44 (s, 1H), 7.30-7.40 (m, 2H), 7.11 (t, 1H), 4.05 (s, 3H); EI/MS 472 m/e (M+); Calcd. for C20H11Cl2F4N3S: C, 50.9; H, 2.35; N, 8.90; Found: C, 50.9; H, 2.49; N, 8.82.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1.CO>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(C(F)(F)F)cc4)c3C2=O)C(=O)N1
Yield: 76.5 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.6 g, 2.2 mmol) and 4-(trifluoromethyl)benzoyl chloride (1 g, 4.8 mmol) in THF (20 mL) was heated to reflux for 15 h. The solvent was removed in vacuo to give a solid. The solid was slurried in methanol (20 mL) for 2 h. The suspension was filtered and washed with ether (15 mL) then methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-trifluoromethyl-benzamide as a white solid (750 mg, 77% yield): mp, 213-215° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.5 Hz, 1H, NCH), 7.72 (d, J=7.2 Hz, 1H, Ar), 7.90-8.02 (m, 3H, Ar), 8.16-8.19 (m, 2H, Ar), 8.49 (d, J=8.4 Hz, 1H, Ar), 10.58 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 118.88, 119.36, 119.32, 123.76 (q, JC-F=271 Hz); 125.99 (q, JC-F=3.6 Hz), 127.10 128.37, 131.54, 132.16 (q, JC-F=32 Hz), 136.00, 136.26, 13721, 164.05, 166.59, 167.65, 169.68, 172.73; Anal Calcd for C21H14N3O5F3: C, 56.64; H, 3.17; N, 9.44; F, 12.80. Found: C, 56.25; H, 3.05; N, 9.32; F, 12.69.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nccnc2c1
Product: O=C(Cl)c1ccc2nccnc2c1

Procedure:
A mixture of quinoxaline-6-carboxylic acid (2 g, 11.49 mmol) and thionyl chloride (30 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness using a rotary evaporator to afford quinoxaline-6-carboxylic acid chloride (crude quantitative). A solution of the above acid chloride (11.49 mmol) in DCM (50 mL) and pyridine (20 mL) was mixed with N,O-dimethyl hydroxylamine HCl salt (2.24 g, 23 mmol) and stirred at room temperature for 12 hours. The reaction was quenched by adding aqueous HCl (50 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield quinoxaline-6-carboxylic acid methoxy-methyl-amide (2 g, 80%). To a solution of the above Weinreb amide (2.0 g, 9.2 mmol) in THF (30 mL) at 0° C. was added methyl magnesium bromide (3.9 mL, 11.6 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then 1 hour at room temperature, quenched by adding aqueous HCl (20 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield 6-acetylquinoxaline (1.17 g, 74%). A solution of 2-chloronicotinic acid ethyl ester (5.0 g, 27 mmol) in MeOH (25 mL) was mixed with sodium methoxide (25.6 mL, 112.5 mmol) and stirred at reflux for 12 hours. The reaction was quenched by adding water (100 mL), extracted with DCM (3×100 mL), concentrated using a rotary evaporator to afford 2-methoxynicotinic acid methyl ester (3.2 g, 71%). A solution of 6-acetylquinoxaline (0.62 g, 3.6 mmol), 2-methoxynicotinic acid methyl ester (0.64 g, 3.8 mmol), and sodium hydride (0.46 g, 11.4 mmol) in THF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL) and AcOH (20 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was re-dissolved in DCM (5 mL) and MeOH (3 mL) and was diluted with Hexanes (50 mL). The solid was removed by filtration and the filtrate was concentrated to afford the diketo compound (0.7 g, 60%). A solution of the above diketone (0.4 g, 1.3 mmol) in AcOH (50 mL) and sulfuric acid (conc., 15 drops) was stirred at reflux for 1 hour. Most of the solvent was removed using a rotary evaporator. The residue was re-dissolved in MeOH and neutralized with potassium carbonate to pH=8. The solid residue was removed by filtration, washed with MeOH and DCM. The filtrate was extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator. The solid residue was purified by column (SiO2, Hexanes/EtOAc/MeOH=2:2:1) to afford 2-(quinoxalin-6-yl)-4H-pyrano[2,3-b]pyridin-4-one (90 mg, 24%); MS (ES) m/z: 276 (M+1); MP 272.3-274.8° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH:9]1[CH:14]=[CH:13][C:12]([P-:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[K+]>C1COCC1>[C:16]1([P:15]([C:12]2[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=2)[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 140 mg (0.15 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 1.27 g (10.0 mmol) of 4-chlorotoluene, and 10.0 mmol of KPPh2 in 30.0 mL of THF. The resulting mixture was refluxed for 17 h before the reaction was cooled to room temperature, quenched with with 20 mL of H2O. The phosphorus-31 NMR spectrum of the reaction mixture at this point showed the δ32.1 [˜10%, Ph2PH(O)] and −5.0 (˜90%, MeC6H4-PPh2) resonances.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH2:46][CH2:45][C:44]=3[N:43]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=3)[C:42](=[O:61])[N:41]2[CH2:62][C:63](O)=[O:64])=[CH:36][CH:35]=1)#[N:33].N>CN(C)C=O>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH2:46][CH2:45][C:44]=3[N:43]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:59])([F:60])[F:58])[CH:52]=3)[C:42](=[O:61])[N:41]2[CH2:62][C:63]([NH2:8])=[O:64])=[CH:36][CH:35]=1)#[N:33]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38 mg, 100 μmol) and triethylamine (70 μL, 500 μmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32, 47 mg, 100 μmol) in N,N-dimethylformamide (0.5 mL). After 20 min ammonia (0.5 M in 1,4-dioxane, 200 μL, 100 μmol) is added, and the mixture is stirred at room temperature for 2 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 29 mg; ESI mass spectrum [M+H]+=469; Retention time HPLC: 0.84 min (Z018_S04).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Cl:7][CH2:8][CH2:9]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)C>[C:1]([O:6][CH2:9][CH2:8][Cl:7])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: OCCCl
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)C(=O)OCCCl
Temperature: 25 °C

Procedure:
2-Chloroethyl pyruvate was prepared as follows: pyruvic acid (8.8 g, 100 mmol), 2-chloroethanol (10.45 g, 130 mmol) and p-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) in 40 mL of benzene were heated under reflux with azeotropic dehydration for 5 h. The mixture was cooled to room temperature and diluted with 70 mL of diethyl ether. This organic solution was washed with 100 mL of saturated aqueous NaHCO3 and 100 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give 2-chloroethyl pyruvate in quantitative yield, slightly contaminated with benzene and diethyl ether (as determined by 1H NMR). Aliquots used for biological analyses were cleared of diethyl ether and benzene by short path vacuum distillation.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([CH2:16][NH:23][C:24]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=3)[CH2:8]2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
To a stirred and chilled (10°-20° C.) solution of 0.04 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of methylene chloride was added dropwise 6.12 g (0.046 mole) of benzyl isocyanate. The reaction mixture was stirred at room temperature for 2 hr and was filtered. The filter cake was washed with petroleum ether (2×50 ml), dilute aqueous sodium bicarbonate (2×50 ml), and water (2×50 ml), yielding 12 g (86%). Recrystallization twice from ethyl acetate gave 9.0 g of clear white flakes, m.p. 173.5°-175° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:17][CH:18]=[CH2:19])[C:9]2[C:14]([C:15]=1[NH2:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[Cl:21][CH2:22][C:23]([NH:16][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][CH:18]=[CH2:19])[C:7](=[O:20])[C:6]=1[C:4]([OH:3])=[O:5])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: C=CCn1c(=O)c(C(=O)OCC)c(N)c2cccnc21
Product: C=CCn1c(=O)c(C(=O)O)c(NC(=O)CCl)c2cccnc21

Procedure:
A stirred mixture of 4 g. of 1-allyl-4-amino-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 30 ml. of chloroacetyl chloride was heated under reflux for 1 hour. The chloroacetyl chloride was evaporated in a rotary evaporator and the residue was triturated with 20 ml. of ethyl acetate. The insoluble material was collected and was recrystallized from ethyl acetate to give 1.2 g. of product, m.p. 145°-148° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].B1(C=C)OB([CH:22]=[CH2:23])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)C.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>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH:22]=[CH2:23])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution of 5,6-dichloronicotinic acid tert.-butyl ester (5.00 g, 20.0 mmol), and 2,4,6-trivinylcyclotriboroxane pyridine complex (9.700 mg, 40 mmol) in dioxane (30 mL), a solution of 2 M aq. K2CO3 (6 mL) followed by Pd(PPh3)4 (620 mg, 0.38 mmol) and triphenylphosphine (620 mg, 3.8 mmol) is added. The mixture is stirred at 100° C. for 2 h, cooled to rt and diluted with diethyl ether (200 mL). The mixture is extracted with 1M aq. NaOH (2×50 mL) and brine (50 mL). The org. phase is dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EA-heptane) to give 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester (4.0 g) as a yellow oil; LC-MS: tR=1.05 min, [M+1+CH3CN]+=281.36.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([O-])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>O>[Cl:24][S:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)Cl)cc2)cc1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
4-(4-Nitrobenzyl)-phenylmethanesulfonic acid sodium salt (2.29 g) was combined with phosphorus pentachloride (1.45 g). The mixture was heated to 90° C. for 5 minutes, poured into water, and extracted with dichloromethane (3×20 mL). Solvents were evaporated to give 4-(4-chlorosulfonylmethylbenzyl)-nitrobenzene as an impure yellow solid (0.63 g). This product was used directly in the next step.
Reaction SMILES: CC1C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.FC(F)(F)C1C=CC=CC=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1[C@@H:40]1[CH2:51][CH2:50][C:49](=[O:52])[C:43]2=[N+:44]([O-])[CH:45]=[CH:46][CH:47]=[C:42]2[CH2:41]1.[CH3:53][C:54]([NH2:57])([CH3:56])[CH3:55]>C(OCC)(=O)C.C(Cl)Cl>[C:54]([NH:57][C:45]1[N:44]=[C:43]2[C:49](=[O:52])[CH2:50][CH2:51][C@@H:40]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:33]=3[F:32])[CH2:41][C:42]2=[CH:47][CH:46]=1)([CH3:56])([CH3:55])[CH3:53]
Reactant: O=C1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)Nc1ccc2c(n1)C(=O)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
At 0° C., the 4-methylbenzenesulfonic anhydride (0.930 g, 2.85 mmol) was added to the trifluoro-toluene (3 mL)/CH2Cl2 (3.00 mL) suspension of (R)-6-(2,3-difluorophenyl)-9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (0.412 g, 1.424 mmol) and 2-methylpropan-2-amine (0.604 mL, 5.70 mmol). The reaction was stirred at 0° C. for 30 min before diluted with ethyl acetate. The crude was washed by NaOH (1N) twice and the ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column by ethyl acetate in hexane from 0 to 40% to 60% gave the desired product (0.1861 g, 38%). MS (ESI)[M+H+]=345.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 (d, J=8.56 Hz, 1H) 6.95-7.10 (m, 2H) 6.82-6.95 (m, 1H) 6.60 (d, J=8.56 Hz, 1H) 4.95 (br. s., 1H) 3.45-3.58 (m, 1H) 2.91-3.05 (m, 3H) 2.73-2.85 (m, 1H) 2.13-2.27 (m, 1H) 1.95-2.11 (m, 1H) 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH:19]([OH:23])[CH2:20][NH:21][CH3:22])[S:9]1(=[O:25])=[O:24].[C:26]([O:30][C:31](=[O:33])[NH2:32])([CH3:29])([CH3:28])[CH3:27].F[B-](F)(F)F.C[O+](C)C.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][C@H:19]([O:23][CH3:26])[CH2:20][NH:21][CH3:22])[S:9]1(=[O:25])=[O:24].[C:26]([O:30][C:31](=[O:33])[NH2:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CNCC(O)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: CC(C)(C)OC(N)=O
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Solvent: ClCCl
Product: CNC[C@H](CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O)OC
Yield: 162.6 %

Procedure:
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol-carbamic acid tert-butyl ester (75 mg, 0.161 mmol), trimethyloxonium tetrafluoroborate (71 mg, 0.483 mmol), proton sponge (121 mg, 0.564 mmol) and 4A molecular sieves were stirred in dichloromethane (5 mL) in a sealed vial at room temperature for 18 hr. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-50% ethyl acetate in hexane to afford 0.065 g of (2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2-methoxy-N-methylbutan-1-amine-carbamic acid tert-butyl ester as a clear oil. This material was dissolved in diethyl ether and methanol and 4N HCl in dioxane was added a precipitate formed. The mixture was filtered to afford 0.050 g of (2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2-methoxy-N-methylbutan-1-amine as a brown solid.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])(O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(O)(c2cccc(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CC=C(c2cccc(F)c2F)CC1
Temperature: 30 °C
Yield: 92.7 %

Procedure:
The compound (8) (215.1 g), p-toluenesulfonic acid (6.5 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (500 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The product obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 186.6 g of 4-pentyl-(2,3-difluorophenyl)-cyclohexene (9). The yield based on the compound (8) was 92.7%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:31]([C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:21]=1[O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Methyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoate (520 mg, 0.002 mol), 4-chloro-3-nitrobenzotrifluoride (442 μL, 0.003 mol) and potassium carbonate were mixed in dimethylformamide (20 mL) at 150° C., under argon, for 16 h. The mixture was filtered, the solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, (CD3)2SO) δ8.38 (d, 1H), 7.98 (d, 1H), 7.89 (dd, 1H), 7.78 (dd, 1H), 7.28 (d, 1H), 6.87 (d, 1H) 3.65 (s, 3H), 3.29 (s, 2H), 1.79 (s, 3H), 1.38 (s, 6H), 0.68 (s, 6H).