Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([NH:9][C@@H:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11]([OH:13])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:25][C:26]([F:40])([F:39])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:35][C@@H:36]([NH2:38])[CH3:37])=[CH:30][CH:29]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:37][C@H:36]([NH:38][C:11]([C@@H:10]([NH:9][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])[CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:16])=[O:13])[CH2:35][NH:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:39])[F:40])=[CH:33][CH:32]=1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Yield: 28.6 %

Procedure:
2-(R)-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (73 mg, 0.21 mmol, 1.0 eq.), N1-(4-Trifluoromethoxy-phenyl)-(S)-propane-1,2-diamine from Scheme 1a (48 mg, 0.21 mmol, 1.0 eq.), EDC (59 mg, 0.31 mmol, 1.5 eq.), and HOBT (38 mg, 0.25 mmol, 1.2 eq.) were dissolved in CH2Cl2 at room temperature. N-methylmorpholine (225 μL, 2.05 mmol, 10 eq.) was added via syringe and the reaction was monitored to completion by LC/MS. The solvent was evaporated and the reaction was purified by mass-directed HPLC and provided 44 mg (0.06 mmol, 31%) of a off-white solid as a mono-TFA salt: HPLC-MS calcd. for C25H31F3N4O6S (M+H+) 573.2, found 573.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=2)[C:14]1=[O:26].O=[C:46]1C2C(=CC=CC=2)CC(=O)N1CC(Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:43][C:6]1[CH:5]=[N+:4]([O-:44])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[CH2:46][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:26]
Reactant: O=C(Cl)CN1C(=O)Cc2ccccc2C1=O
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1C(=O)Cc2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (40 mg, 0.062 mmol) was dissolved in DCM (2 ml), and added with 2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)acetyl chloride (163 mg, 0.686 mmol) and DMAP (84 mg, 0.686 mmol). The reaction was stirred at RT overnight and quenched by addition of HCl. The solution extracted with DCM and washed with NaHCO3 sat. sol., then dried over Na2SO4 and the solvent removed under reduced pressure. The crude was purified by preparative HPLC (Method 2) to yield the titled compound (30.0 mg, 52% yield).). 1H NMR (400 MHz, acetone) ppm 8.19 (s, 2H), 8.09-8.15 (m, 1H), 7.67-7.79 (m, 1H), 7.44-7.61 (m, 2H), 7.15-7.24 (m, 2H), 7.01-7.09 (m, 1H), 6.94 (t, J=75.00 Hz, 1H), 6.01-6.25 (m, 1H), 4.68 (s, 2H), 4.24 (s, 2H), 4.03 (dd, J=6.84, 2.87 Hz, 2H), 3.42-3.60 (m, 1H), 3.20-3.38 (m, 1H), 1.24-1.46 (m, 1H), 0.65 (dd, J=8.16, 1.54 Hz, 2H), 0.43 (d, J=5.73 Hz, 2H); MS/ESI+ 621.3 [MH]+
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[C:12]([C:14]2[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH:13]=1.N1C=CC=CC=1.Cl>ClCCl>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[O:23][C:11]1[CH:10]=[CH:9][C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[C:14]1[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c(F)cc1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 5-[5-amino-2-(2,4-difluorophenoxyl)phenyl]-4-fluoro-1-methylpyridin-2-one (72 mg, 0.21 mmol) and pyridine (50 μL, 0.63 mmol) in dichloromethane (500 μL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 2 h, it was treated with 1N HCl (3 mL) and extracted with dichloromethane (3×10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 0-10% MeOH in dichloromethane) to afford the desired product, N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide (66 mg, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.26 (m, 3H), 3.07-3.16 (m, 2H), 3.45 (s, 3H), 6.22-6.33 (m, 1H), 6.82-6.93 (m, 1H), 7.01-7.16 (m, 2H), 7.18-7.28 (m, 2H), 7.38-7.49 (m, 1H), 7.95-8.05 (m, 1H), 9.77-9.87 (s, 1H). LCMS (M+H)+ =439.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[N:7][C:8](Cl)=[C:9]([CH:12]=1)[C:10]#[N:11]>C(O)C>[Br:4][C:5]1[CH:12]=[C:9]2[C:10]([NH2:11])=[N:3][NH:2][C:8]2=[N:7][CH:6]=1
Reactant: NN
Reactant: N#Cc1cc(Br)cnc1Cl
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2ncc(Br)cc12

Procedure:
Hydrazine hydrate (19 ml, 391 mmol) was added to a stirred solution of 5-bromo-2-chloronicotinonitrile (34 g, 156 mmol) in ethanol (300 ml). The reaction mixture was stirred at reflux for 4 hours then the solvent was removed in vacuo. Water was added and the resulting solids were filtered, washed with water, and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]2[C:16]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:17][N:18]([CH2:28][CH3:29])[C:19]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:10][CH:11]=[CH:12][O:13]C)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:15]2[C:16]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:17][N:18]([CH2:28][CH3:29])[C:19]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:10][CH2:11][CH:12]=[O:13])=[CH:7][CH:8]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CC=COC)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccn2)c(C(CCC=O)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
A solution of 2 M aqueous hydrogen chloride (1.00 mL, 2.00 mmol) was added in one portion to a solution of tert-butyl (4-(1-(4-bromophenyl)-4-methoxybut-3-en-1-yl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.0708 g, 0.118 mmol) and THF (2.00 mL) under air. After about 45 min, 5 mL saturated aqueous NaHCO3 (5 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using a gradient of 0-50% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford tert-butyl (4-(1-(4-bromophenyl)-4-oxobutyl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.0450 g, 0.0880 mmol, 74%) as a sticky, pale yellow solid. LC-MS (Table 1, Method g) Rt=2.72 min; m/z 513 and 515 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH3:6].[Cl:7][CH2:8][CH2:9][S:10](Cl)=[O:11]>CCOCC>[Cl:7][CH2:8][CH2:9][S:10]([O:1][CH2:2][CH2:3][S:4][CH2:5][CH3:6])=[O:11]
Reactant: CCSCCO
Reactant: O=S(Cl)CCCl
Solvent: CCOCC
Product: CCSCCOS(=O)CCCl
Temperature: 25 °C

Procedure:
A solution of ethyl 2-hydroxyethyl sulfide (10.6 w) in dry ether (50 v) was slowly added to 2-chloroethanesulfinyl chloride (14.7 w) in dry ether (200 v) maintained at about -10° under a nitrogen atmosphere. Upon warming to ambient temperature, the reaction mixture was evaporated under reduced pressure. The residual oil was passed through a wiped film molecular still to yield 2-(ethylthio)ethyl 2-chloroethanesulfinate (15.4 w) boiling at 95-100° under reduced pressure (1 × 10-4 torr).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:23]([NH2:25])[CH3:24]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:23][CH3:24])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCN
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CCNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Yield: 92.7 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.573 mmol), and ethanamine (0.286 mL, 0.573 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-N-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (190 mg, 0.531 mmol, 93% yield). LC-MS (M+H)+=358.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].[Cl:19]N1C(=O)CCC1=O>ClCCl.CCOCC>[Cl:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2Cl)CC1
Reaction time: 6 h
Yield: 63.1 %

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.5 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.301 g) and stirred for 6 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane, afforded the title compound (0.36 g). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H), 2.52 (4H), 3.79 (4H), 7.21 (1H), 7.31 (1H), 7.38 (1H), 7.64 (1H), 9.05 (1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:16][C@H:15](CS([O-])(=O)=O)[CH2:14][C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH:16]=[CH:15][CH2:14][C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(Cl)c2C(=O)N2C[C@H](CS(=O)(=O)[O-])C[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2C=CC[C@@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 17.0 g (49.3 mmol) of (2R,11aS)-6-chloro-2,3,5,10,11,11a-hexahydro-5,11-dioxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-yl-methanesulphonate in 80 ml of dry dimethylformamide is treated with 4.3 g (98.6 mmol) of sodium hydride (55 percent oil dispersion), the mixture is stirred at 45° for a further 2 hours, then poured into 300 ml of ice-water, neutralized with 5.6 ml of glacial acetic acid and extracted four times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. By crystallization from ethanol there is obtained (S)-6-chloro-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 249°-251°.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=O>O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH:31]=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
Betulinol was placed in a thermostated reactor, and acetone, in an amount of 100-110 ml per gram of betulinol, was added with stirring. An oxidizing mixture of CrO3/H2SO4 (molar ratio of 2:3, respectively) was then slowly poured into the reactor 20 with stirring. The reaction mixture was brought to reflux and maintained at reflux for 2.5-3 hrs. The reaction mixture was then cooled and water was added, resulting in the formation of a sediment. The sediment was filtered and recrystallized from ethanol. The resulting solid contained 93-95% of betulonic aldehyde and melted at a temperature from 154-156° C. The yield of purified betulonic aldehyde was 65%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][C@@H:33]([C@@H:40]1[C@@:44]2([CH3:62])[CH2:45][CH2:46][CH:47]3[C@@:52]4([CH3:61])[CH2:53][CH2:54][CH:55]([O:57][C:58](Cl)=[O:59])[CH2:56][C:51]4=[CH:50][CH2:49][CH:48]3[CH:43]2[CH2:42][CH2:41]1)[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:58]([O:57][CH:55]1[CH2:56][C:51]2[C:52]([CH3:61])([CH:47]3[CH:48]([CH2:49][CH:50]=2)[CH:43]2[C:44]([CH3:62])([CH:40]([CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:41][CH2:42]2)[CH2:45][CH2:46]3)[CH2:53][CH2:54]1)=[O:59])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C(C(C)CCCC(C)C)CCC32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) is taken up in dichloromethane. The suspension is cooled to 0° C. on ice. To the suspension diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) is added. To the resulting solution cholesteryl chloroformate (6.675 g, 14.8 mmol) is added. The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane and ished with 10% hydrochloric acid. The product is purified by flash chromatography (10.3 g, 92%).
Reaction SMILES: CC(C)([O-])C.[K+].FC(F)(S([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CN(C=O)C.[Cl:36][C:37]1[C:46](O)=[C:45]([S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>O>[Cl:36][C:37]1[C:46]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[C:45]([S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1O
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(F)(F)C(F)F
Temperature: 120 °C

Procedure:
1.200 g (4.3 mmol) of potassium tert-butoxide and 1.917 g (4.3 mmol) of 2,2,3,3-tetrafluoropropyl perfluorobutanesulfonate were introduced into 30 ml of DMF in a vessel. At RT, 1200 g (4.3 mol) of methyl 2-chloro-3-hydroxy-4-ethylsulfonylbenzoate were added and the mixture was then heated at 120° C. for 7 h. It was subsequently introduced into water and subjected to extraction with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Drying under an oil pump vacuum gave methyl 2-chloro-3-(2,2,3,3-tetrafluoropropyloxy)-4-ethylsulfonylbenzoate as a brown oil.
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[N:9]=[C:8]2[S:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]4)=[CH:15][C:14]=3[F:28])=[N:12][C:7]2=[CH:6][CH:5]=1.C([Sn](CCCC)(CCCC)[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[CH2:35])CCC>CN(C=O)C.CCOC(C)=O.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:28][C:14]1[CH:15]=[C:16]([CH2:19][N:20]2[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]2)[CH:17]=[CH:18][C:13]=1[C:11]1[S:10][C:8]2[C:7]([N:12]=1)=[CH:6][CH:5]=[C:4]([C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[CH2:35])[N:9]=2
Reactant: C=C(c1ccc(F)cc1)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(Cl)nc4s3)c(F)c2)C1
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccc(F)cc1)c1ccc2nc(-c3ccc(CN4CC(C(=O)OC)C4)cc3F)sc2n1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A slurry of cesium fluoride (0.310 g, 2.04 mmol), copper(I) iodide (0.0194 g, 0.102 mmol), tetrakis(triphenylphosphine) palladium (0) (0.0590 g, 0.0510 mmol), methyl 1-((4-(5-chlorothiazolo[5,4-b]pyridine-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate (0.400 g, 1.02 mmol), tributyl(1-(4-fluorophenyl)-vinyl)stannane (0.504 g, 1.22 mmol) in 2 mL DMF was sealed and heated to 45° C. overnight. The reaction mixture became purple/black and was allowed to stir at ambient temperature for 24 h. The reaction mixture was diluted with EtOAc and filtered through celite, then the filtrate was washed with water. The water layer was removed, and the EA layer was treated with DCM until only slightly cloudy, the organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, 0-100% EA/hexanes to give methyl 1-((3-fluoro-4-(5-(1-(4-fluorophenyl)vinyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as an orange solid. MS (ESI) m/z: calculated: 477.1; Observed: 478.1 (M++1).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[CH2:11][CH2:12]2)[CH2:7][CH2:6][C:5]1=O)[CH2:2][CH3:3].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.COC1C=CC(O)=CC=1>[O:19]=[C:16]1[NH:20][C:10]2[CH2:9][C@H:8]3[C@H:13]([CH2:12][C:11]=2[CH2:18][CH2:17]1)[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7]3
Reactant: C=CC(N)=O
Reactant: CCCN1C(=O)CC[C@@H]2CC(=O)CC[C@H]21
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN1CCC[C@H]2CC3=C(CCC(=O)N3)C[C@@H]21
Yield: 36.6 %

Procedure:
A mixture of (±)-trans-1-propyl-6-oxo-decahydroquinolone (30.0 g, 154 mMol), acrylamide (32.8 g, 462 mMol), p-toluenesulfonic acid monohydrate (35.2 g, 185 mMol), and p-methoxyphenol (500 mg) in toluene (1000 mL) was heated to reflux, water being collected in a Dean-Stark trap. After 17 hr of reflux, the reaction was poured into dilute NaOH solution and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown foam. Recrystallization (ethyl acetate/hexanes) provided the desired product as a tan solid (14.0 g, 37% yield). Purification of the mother liquors by flash chromatography (2:1 THF: hexanes, 0.5% NH4OH) provided additional product (Rf =0.40, 2.6 g, 7% yield). Recrystallization of this material (ethyl acetate) provided analytically pure material. m.p. =183.0°-184.0°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:17][CH2:16]1)[CH3:2].C(=O)(O)[O-].[Na+].[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[N:55][N:54]=[N:53]2)=[CH:47][C:43]=1[C:44](Cl)=[O:45].CO.ClCCl>C(OCC)(=O)C.CCCCCC.CC(C)=O.C(OCC)(=O)C>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[N:55][N:54]=[N:53]2)=[CH:47][C:43]=1[C:44]([N:26]1[CH2:27][CH2:28][C:24]([CH2:23][CH2:22][N:18]2[CH2:19][CH2:20][CH2:21][N:15]([C:7]3[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16][CH2:17]2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25]1)=[O:45]
Reactant: COc1ccc(Cn2cnnn2)cc1C(=O)Cl
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(Cn5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.69 g, 1.49 mmol) and sodium bicarbonate (0.93 g, 11.07 mmol) in acetone/water (1/1, 40 mL). Cool in an ice bath. Add a solution of 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl chloride (0.38 g, 1.49 mmol) in acetone (25 mL). After 18 hours, dilute the reaction mixture with ethyl acetate and extract twice with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate and then methanol/dichloromethane/concentrated aqueous ammonia 10/90/0.1 give the title compound: Rf=0.82 (silica gel, methanol/dichloromethane/concentrated aqueous ammonia 10/90/0.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>C1(C)C=CC=CC=1.CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)([CH2:35][S:36]([OH:39])(=[O:38])=[O:37])[NH:13][CH2:12][CH2:11]2
Reactant: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Reactant: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)cc1)(CS(=O)(=O)O)NCC2
Temperature: 90 °C

Procedure:
The compound 3 is suspended in toluene and heated to 80-100° C. After addition of 1.5 equivalents phosphorus oxychloride the mixture is heated for 6 hours to 80-100° C. and then cooled within 3 hours to 20° C. The suspension is added to water while maintaining the pH of the aqueous layer during addition and subsequent stirring between 7-8 by addition of a sodium hydroxide solution. The mixture is stirred until all precipitate is dissolved. After phase separation the water is removed by azeotropic distillation. Then 1.0 equivalent of methanesulfonic acid is added and the formed suspension stirred for some time. At this point in time parts of the solvent may be replaced by acetone, and then the mixture is slowly cooled to 0-10° C. and stirred at this temperature for another couple of hours. After filtration the product is washed with toluene and dried in vacuo.