Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=O.[Na+].[Na+].[C:15]1(B(O)O)[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CO.[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>[CH:7]([C:5]1[O:6][C:2]([C:15]2[CH:20]=[CH:19][C:18]([C:5]3[O:6][C:2]([CH:9]=[O:12])=[CH:3][CH:4]=3)=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)o1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)o3)cc2)o1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a stirred solution of 5-bromofuran-2-carboxaldehyde (10 mmol), and tetrakis(triphenylphosphine) palladium (400 mg) in toluene (20 ml.) under a nitrogen atmosphere was added 10 mL of a 2 M aqueous solution of Na2CO3 followed by 1,4-phenylenebisboronic acid (5 mmol) in 6 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 12 h. The solvent was evaporated, the precipitate was partitioned between methylene chloride (300 mL) and 2 M aqueous Na2CO3 (15 mL) containing 5 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 11 in 93% yield; mp 233-234° C. (EtOH). 1H NMR (DMSO-d6); δ 9.64 (s, 2H), 8.01 (s, 4H), 7.70 (d, J=3.6 Hz, 2H), 7.43 (d, J=3.6 Hz, 2H). MS (ESI) m/e (rel. int.): 266 (M+, 100), 238 (5), 209 (25). Anal. Calc. for C16H10O4: C %, 72.16; H %, 3.78. Found C %, 72.41; H %, 3.93.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH:25]=[O:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To the solution of (4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)methanol (30 mg, 0.081 mmol) in 2 ml of THF and 2 ml of DCM was added Dess-Martin Periodinane (38 mg, 0.089 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The crude reaction mixture diluted with ethyl acetate (60 ml), washed with saturated sodium bicarbonate (2×15 ml), brine (1×15 ml), dried with Na2SO4, filter and concentrated in vacuo to give 4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinaldehyde as solid (29 mg). ES/MS m/z 386.1 (MH+) as the hydrate (+18).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-:10].C[CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[C:13](Cl)=[O:14].[OH-].[Na+]>O1CCCC1.O>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:12][C:13]([OH:14])=[O:10])=[O:23]
Reactant: Nc1cc(Cl)ccc1O
Reactant: [OH-]
Reactant: CC(CCCCCCC(=O)Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCC(=O)Nc1cc(Cl)ccc1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To a cold solution of 2-amino-4-chlorophenol (2.56 g, 17.83 mmol) in tetrahydrofuran (40 mL) was added a solution of hydroxide (0.72 g, 18 mmol) in water (15 mL). The mixture was stirred at 0° C. for 5 min. A solution of methyl azeloyl chloride (3.9 g, 17.67 mmol) in tetrohydrofuran (10 mL) was added dropwise to this mixture. The resulting mixture was stirred at 0° C., then gradually warmed to room temperature, and stirred at room temperature overnight. A solution of sodium hydroxide (2N, 25 mL) was added to the reaction mixture. The mixture was stirred at room temperature and monitored by TLC. When the starting material was no longer visible, the reaction mixture was concentrated in vacuo. The residue was acidified to pH 2, and the precipitated solid was collected by filtration. This crude product was dissolved in methanol (50 mL), decolorized with activated charcoal, and filtered. A small amount of acetone and water was added to the filtrate, and the mixture refrigerated overnight. A solid was formed, collected by filtration, washed with water, and dried to give the product as a pale yellow, crystalline solid (3.0 g, 54%); mp 117°-118° C.; 1H NMR (DMSO-d6) δ7.96 (d. J=2.5 Hz, 1H), 6.95 (dd, J=8.6, 2.6 Hz, 1H), 6.85 Hz, 1H), 2.39 (t, J=7.3 Hz, 2H), 2.19 (t, J=7.3 Hz, 2H), 1.40-1,61 (m, 4H), 1.20-1.35 (m, 6H). Anal. Calcd for C5H20CINO4 :C, 57.42; H, 6.42; N, 4.46. Found: C, 57.24; H, 6.30; N, 4.41.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([PH2:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]1COC[CH2:14]1>O>[CH3:5][C@@H:4]1[CH2:3][CH2:2][C@@H:13]([CH3:14])[P:12]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: Pc1ccccc1
Reactant: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@H](C)P1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
One equivalent of n-BuLi (8.9 ml, 1.6 M. solution in n-hexane) is added slowly to a solution of 1.57 g phenylphosphine (14.3 mmol) in 100 ml of THF at −78° C. This is then stirred for a further two hours at room temperature. After cooling again to −78° C., one equivalent of the cyclic sulfate 1 in 10 ml of THF is added via a cannula and the reaction is allowed to end by stirring at 25° C. for 3 hours. Before adding a further 1.2 eq. of n-BuLi (9.8 ml) via syringe, the mixture is cooled again, n-BuLi is added and stirring is continued overnight. For the work-up, the solvent was drawn off in vacuo and the residue taken up in 5 ml of water and extracted with 50 ml of methylene chloride. After the phase separation the solvent is removed and the residue is distilled in vacuo. An almost colourless syrup is obtained in a yield of 71% (1.95 g).
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([O:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]([F:32])=[C:23]([NH:25]C(=O)C(F)(F)F)[CH:24]=1)[N:12]=2)(=[O:7])[CH3:6].O>C(O)C>[NH2:25][C:23]1[C:22]([F:32])=[CH:21][C:20]([Cl:33])=[C:19]([CH:24]=1)[O:18][C:13]1[N:12]=[C:11]2[S:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:17][C:16]2=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc2ccc(Oc3cc(N)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.1 %

Procedure:
To a solution of sodium borohydride (3.38 g, 100 mmol) in ethanol (60 mL) was added dropwise methanol (40 mL) under ice-cooling, and N-(5-{[2-(acetylamino) [1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-4-chloro-2-fluorophenyl)-2,2,2-trifluoroacetamide (2.16 g, 4.81 mmol) was added in portions thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (400 mL), and the mixture was extracted with ethyl acetate (200 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether, collected by filtration, and dried under reduced pressure to give the title compound (3.26 g, 68%) as white powder crystals.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:4](=[O:15])[CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:30][NH:31]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[C:30]([CH:16]([C:3]3[C:4](=[O:15])[O:5][CH:6]([CH2:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:2]=3[OH:1])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:31]2)=[CH:27][CH:26]=1
Reactant: O=C1C=C(O)C(CCc2ccccc2)O1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NCCc1c(C(C2=C(O)C(CCc3ccccc3)OC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 4-hydroxy-5-phenethyl-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Example 18.1.) to give the title compound as pale red solid. MS: 511.1 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:12])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(OCC)C>[F:1][C:2]([F:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:21])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (2.0 g; 0.0114 mole) and N,N-dimethylformamide (0.08 g) in 20 ml of dry diethyl ether was cooled to 0° C. A solution of oxalyl chloride (2.17 g; 0.017 mole) in 2 ml of dry diethyl ether was added to the reaction mixture during a 20 minute period. Upon complete addition the mixture was allowed to warm to room temperature and stir for two hours. The mixture was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in 5 ml of dry diethyl ether and the solvent removed under reduced pressure to yield trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonylchloride as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][C:13]([NH2:15])=[NH:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].O.[NH2:17]N.[C:19]([NH:22][CH:23]([CH3:31])[C:24](=O)[C:25](OCC)=[O:26])(=[O:21])[CH3:20]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:12][C:13]1[NH:15][C:25](=[O:26])[C:24]([CH:23]([NH:22][C:19](=[O:21])[CH3:20])[CH3:31])=[N:17][N:14]=1
Reactant: COc1ccc(CC(=N)N)cc1OC
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: NN
Agent: Cl
Solvent: O
Product: COc1ccc(Cc2nnc(C(C)NC(C)=O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 7A, 20.0 g (86.7 mmol) of 2-(3,4-dimethoxyphenyl)ethanamidine hydrochloride (Example 5A) are reacted with 5.21 g (104 mmol) of hydrazine hydrate and 24.3 g (130 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate (Example 6A) to give N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO>[OH:20][C:6]1[C:5]([CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:4]([OH:21])[C:3]([O:2][CH3:1])=[C:8]2[C:7]=1[C:12](=[O:13])[CH:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2
Reactant: C1COCCN1
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Reactant: C=O
Solvent: CO
Product: COc1c(O)c(CN2CCOCC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.1 ml), morpholine (8.7 g) was stirred under for 4 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 36.3 g of purity 99.1%. MS: (API-ES) m/z 384.5[M+H]+, 406.5[M+Na]+; 1H NMR (DMSO-d6, 400 MHz) δ 8.07˜8.08 (m, 2H, Ar-2′,6′-H), 7.61˜7.63 (m, 3H, Ar-3′,4′,5′-H), 7.00 (s, 1H, 3-H), 3.87 (s, 3H, 8-OCH3), 3.82 (s, 2H, CH2), 3.65 (s, 4H, CH2), 2.60 (s, 4H, CH2).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=3[Cl:29])=[C:16]([C:30]([O:32]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=3[Cl:29])=[C:16]([C:30]([N:45]3[CH2:46][CH2:47][CH:42]([C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=4)[CH2:43][CH2:44]3)=[O:32])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(C(F)(F)F)ccc1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(C(F)(F)F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 73 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-5-trifluoromethylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.87 g, 5.52 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.37 g, 7.62 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.63 g, 79%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH2:42][CH3:43])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[CH:5][C:6]=4[O:41][CH2:42][CH3:43])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:30]2=[CH:29][CH:28]=1
Reactant: CCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-ethoxy-benzoic acid methyl ester (0.12 g, 0.19 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-ethoxy-benzoic acid as a off white powder (Yield, 0.1 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: On1nnc2ccccc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
A suspension of 2-chloro-5-fluoro-nicotinic acid (2.0 g, 11.39 mmol), HOBt (2.31 g, 17.13 mmol), BOP—Cl (4.37 g, 17.15 mmol), ammonium chloride (1.22 g, 22.86 mmol), DIPEA (12 ml, 66.74 mmol) in DMF (75 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phases were dried over MgSO4, filtrated and evaporated. The crude product was purified by column chromatography (silica gel, EtOAc) to obtain 2-chloro-5-fluoro-nicotinamide (850 mg, 4.9 mmol; 43%) as white solid. MS (m/e): 175.1 [M+H+].
Reaction SMILES: BrC1C=CC=CC=1O[CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].BrC/C=C/C(OCC)=O>>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Sc1ccccc1Br
Reactant: CCOC(=O)C=CCOc1ccccc1Br
Agent: CCOC(=O)/C=C/CBr
Product: CCOC(=O)C=CCSc1ccccc1Br

Procedure:
The title compound was prepared (26.1 g, 82%) in a manner analogous to the preparation of ethyl 4-(2-bromophenyloxy)but-2-enoate (Example 5) by the reaction of 2-bromothiophenol with ethyl 4-bromocrotonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:34]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:35])[C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:34]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)C[C@@H]1CCc1ccc(F)cc1
Yield: 68.2 %

Procedure:
Using a method similar to the method of Example 543, using (S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.339 g, 0.714 mmol), sodium triacetoxyborohydride (0.227 g, 1.07 mmol), and aqueous formaldehyde (0.080 mL, 1.1 mmol) in dichloroethane, and employing a second chromatographic purification, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 2% 2M ammonia in methanol (in hexane) added, gives the title compound (0.238 g). Mass spectrum (APCI+, m/e): 489 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][NH:29][CH:30]([CH3:32])[CH3:31])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[OH:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][N:29]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=1)[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)NNC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), 3-hydroxy-N′-isopropylbenzohydrazide (202.81 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA) (0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (28% EtOAc) and dried so that ivory (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (54 mg, 16.7%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:23]=[C:22]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]3[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=3)[CH:37]=2)[N:21]=1>C1COCC1>[CH2:1]([NH:9][S:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([C:38]2[CH:37]=[C:36]([C:22]3[N:21]=[C:20]([C:19]([F:18])([F:52])[F:53])[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:23]=3)[CH:41]=[CH:40][N:39]=2)[CH:43]=1)(=[O:49])=[O:50])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of phenethylamine (0.36 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.57 g, 97%). MS (ISP) 628.8 [(M+H)+]; mp 201° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([NH:19][CH:20]=[CH:21][CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([NH:11][C@H:12]([C:17]([NH:19][CH:20]1[O:31][CH:21]1[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC=CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1OC1C
Reaction time: 8 h

Procedure:
N-(Cbz-leucinyl)-amino-propene (2.95 g, 9.7 mmol) was dissolved in methylene chloride (100 ml), then mCPBA (5.0 g, 29.1 mmol) was added and the reaction was stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 50% EtOAc: hexanes).
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][C:9](=[O:44])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][S:18]([N:21]2[CH2:42][CH2:41][C:24]3([N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH:36]=[C:37]([F:39])[F:38])[CH2:31][CH2:30]4)[NH:26][C:25]3=[O:40])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[C:12]([CH3:43])[CH:11]=1.Cl>C(O)(C)(C)C.O1CCCC1.COC(C)(C)C>[F:39][C:37]([F:38])=[CH:36][CH2:35][CH:32]1[CH2:33][CH2:34][CH:29]([C:27]2[NH:26][C:25](=[O:40])[C:24]3([CH2:41][CH2:42][N:21]([S:18]([CH2:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]([C:9]([OH:44])=[O:8])=[CH:11][C:12]=4[CH3:43])(=[O:20])=[O:19])[CH2:22][CH2:23]3)[N:28]=2)[CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCC(CC=C(F)F)CC2)NC3=O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(CC=C(F)F)CC1)NC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.2 %

Procedure:
Potassium t-butoxide (15.6 mg) was added to a solution of 4-(2-{2-[4-(3,3-difluoro-allyl)-cyclohexyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl}-ethyl)-3-methyl-benzoic acid methyl ester (25.6 mg, 46.4 μmol) in t-butanol (464 μL) and tetrahydrofuran (464 μL), and the mixture was stirred at room temperature for two days. The reaction mixture was diluted with tert-butyl methyl ether and then adjusted to pH 1 with 2 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was then dried to give 4-(2-{2-[4-(3,3-difluoro-allyl)-cyclohexyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl}-ethyl)-3-methyl-benzoic acid (27.5 mg, 91%).