Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:17]3[CH2:18][CH:19]4[N:24]([S:25]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:23]([C:16]=3[CH:15]=[N:14]2)[CH2:22][CH:21]([C:35](OCC)=[O:36])[CH2:20]4)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:50]2[CH:54]=[C:53]3[CH:55]4[N:61]([S:62]([C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=5)(=[O:64])=[O:63])[CH:59]([CH2:60][C:52]3=[N:51]2)[CH2:58][CH:57]([C:72](OCC)=[O:73])[CH2:56]4)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[C:17]3[CH2:18][CH:19]4[N:24]([S:25]([C:28]5[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=5)(=[O:27])=[O:26])[CH:23]([C:16]=3[CH:15]=[N:14]2)[CH2:22][CH:21]([CH2:35][OH:36])[CH2:20]4)(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([N:50]2[CH:54]=[C:53]3[CH:55]4[N:61]([S:62]([C:65]5[CH:66]=[CH:67][C:68]([Cl:71])=[CH:69][CH:70]=5)(=[O:64])=[O:63])[CH:59]([CH2:60][C:52]3=[N:51]2)[CH2:58][CH:57]([CH2:72][OH:73])[CH2:56]4)(=[O:49])=[O:48])=[CH:45][CH:46]=1
Reactant: CCOC(=O)C1CC2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CC2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C1CC(CO)C2
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C1CC(CO)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium borohydride (10 mg, 0.516 mmol) was added to a solution of ethyl 1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carboxylate and ethyl 2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-6-carboxylate (57) (0.151 mg, 0.258 mmol) in THF (1 mL) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated to give {1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazol-6-yl}methanol and {2,10-Bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazol-6-yl}methanol (58). MS (ESI) 542.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(Br)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-bromo-2-formylbenzonitrile (200 mg, 0.95 mmol) and morpholine (248 mg, 2.85 mmol) in dichloroethane (10 mL), acetic acid (342 mg, 5.7 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (604 mg, 2.85 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (150 mg, 56%).
Reaction SMILES: [F:1][C:2]1([CH2:13]N)[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[CH:3]1[CH2:11]N.C(O)(=[O:17])C.N([O-])=O.[Na+].[OH2:23]>>[F:1][C:2]1([CH2:13][OH:17])[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[CH:3]1[CH2:11][OH:23]
Reactant: O
Reactant: NCC1C(F)=C(F)C=C(F)C1(F)CN
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: OCC1C(F)=C(F)C=C(F)C1(F)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Into a 200 ml-volume flask equipped with a thermometer, a stirring unit, a nitrogen inlet and a reflux condenser, 10.4 g (50.0 mmol) of 2,3,5,6-tetrafluoroxylylenediamine synthesized in Example 1, 50 g of water and 9.0 g (150.0 mmol) of acetic acid were charged, and the mixture was stirred at room temperature for 30 minutes. Subsequently, under cooling of the reactor in a water bath, 21.56 g (125.0 mmol) of an aqueous 40 mass % sodium nitrite solution was added dropwise while keeping the inside of the reaction system at 40° C. or less. At the time when about 30% of an aqueous sodium nitrite solution was charged into the reaction system, insoluble components precipitated in the system and vigorous bubbling occurred. Therefore, the dropwise addition of an aqueous sodium nitrite solution was stopped until the bubbling calmed. After the disappearance of bubbling, the dropwise addition of an aqueous sodium nitrite solution was re-started but bubbling was again generated. The operation of re-starting the dropwise addition of sodium nitrite after the disappearance of bubbling was repeated and after 5 hours and 20 minutes, the dropwise addition was completed. The reaction solution obtained was extracted with 10.0 g of methyl ethyl ketone, the organic: phase was washed with 5.0 g of an aqueous 5 mass % sulfuric acid solution, and then the methyl ethyl ketone was removed by distillation, as a result, 8.9 g of 2,3,5,6-tetrafluorobenzenedimethanol was obtained as white crystals. The purity determined from the GC area in percentage was 97.9% and the yield was 82.9%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[S:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]2=[O:17])#[CH:2].I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CCN(CC)CC.C1COCC1.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.[Cu]I>[CH3:16][C:8]1([CH3:15])[CH2:7][C:6](=[O:17])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([C:1]#[C:2][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:4]=2)[S:9]1
Reactant: C#Cc1cc2c(cc1OC)SC(C)(C)CC2=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2OC)SC(C)(C)CC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of 6-ethynyl-7-methoxy-2,2-dimethylthiochroman-4-one (Compound 208, 217.0 mg, 0.88 mmol) and ethyl 4-iodobenzoate (245.0 mg, 0.89 mmol) in 10.0 mL Et3N and 2 mL THF was purged with argon for 15 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (154.0 mg, 0.22 mmol) and copper(I) iodide (42.0 mg, 0.22 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite using an EtOAc wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (5 to 10% EtOAc/hexanes) of the residual solid afforded 320.0 mg (92%) of the title compound as an orange solid. 1H NMR (300 MHz, CDCQ3)δ: 8.29 (1H, s), 8.03 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 6.70 (1H, s), 4.40 (2H, q, J=7.1 Hz), 3.96 (3H, s), 2.86 (2H, s), 1.50 (6H, s), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8]2(SCCS2)[CH2:7]1)(=[O:3])[CH3:2].O.C([O:28]CC)C>O1CCCC1.CO>[C:1]([O:4][CH2:5][C:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8](=[O:28])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: COc1ccc(OC)c2c1CC(O)(COC(C)=O)CC21SCCS1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c2c1CC(O)(COC(C)=O)CC2=O
Reaction time: 1 h
Yield: 70 %

Procedure:
1.9 g of rac-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 40 ml of tetrahydrofuran were added to a stirred suspension of 6.4 g of mercuric chloride and 6.4 g of mercuric oxide in 200 ml of methanol containing 18 ml of water. After standing at room temperature for 1 hour, ca 150 ml of solvent were removed by evaporation under reduced pressure, 200 ml of dichloromethane were added and the resulting suspension was filtered to remove insoluble material. The filtrate was washed with three 200 ml portions of water, dried over magnesium sulphate and evaporated to give a solid residue. Trituration with diethyl ether gave 1.0 g (70%) of rac-3-acetoxymethyl-1,2,3,4-tetrahydro-3-hydroxy-5,8-dimethoxy-1-oxo-naphthalene in the form of an off-white powder of melting point 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[C:68]([Cl:75])[CH:67]=1>C(Cl)Cl>[C:70]([C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:67][C:68]=1[Cl:75])(=[O:71])[NH2:72]
Reactant: NC(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)c(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 4-amino-2-chloro-benzamide (Chembridge, 58 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 6 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3Br)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Zn](C)[CH3:43].C1(C)C=CC=CC=1>C1COCC1.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>[Cl:39][C:32]1[C:33]([F:38])=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C@H:29]([O:28][C:27]1[C:22]2[O:21][C:20]([CH3:43])=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[C:23]=2[CH:24]=[N:25][C:26]=1[NH2:40])[CH3:30]
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1oc2c(O[C@H](C)c3c(Cl)ccc(F)c3Cl)c(N)ncc2c1-c1cnn(C2CCNCC2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.0299 mmol), 2.0 M Me2Zn in PhMe (0.04 mL, 0.08 mmol), and Pd(PPh3)4 (2.9 mg, 0.0025 mmol) in THF (1 mL) was degassed and refilled with argon (3×), then heated at 100° C. for 30 min using a CEM microwave reactor. The solution was passed through a PL-Thiol SPE cartridge to remove metals. The material was then dissolved in dioxane and EtOH, charged with 4M HCl in Dioxane (0.2 mL) and stirred at rt for 4 h. The solution was concentrated in vacuo, redissolved in DMF (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 2.28-2.39 (m, 4H), 2.43 (s, 3H), 3.16-3.26 (m, 2H), 3.55-3.62 (m, 2H), 4.61 (dt, J=10.0, 5.0 Hz, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.1, 4.8 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H), 7.99 (s, 1H). MS (ES+): m/z 504.06/506.07 (100/71) [MH+]. HPLC: tR=2.73 min (ZQ3, polar—5 min).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccc([N+](=O)[O-])cc32)cc1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=1>CN(C=O)C.O>[O:18]=[C:8]1[N:7]([CH:4]2[CH2:3][CH2:2][N:1]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=3)[CH2:6][CH2:5]2)[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9]1
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
700 mg (2.85 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 470 μL (2.73 mmol) DIPEA were added to 500 mg (2.68 mmol) ethyl 6-chloropyrimidine-4-carboxylate in 10 mL DMF and the reaction mixture was stirred for 1 h at RT. The reaction mixture was diluted with water and stirred for 30 min. The precipitate was suction filtered, washed with water and dried at 50° C. in the CAD.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][O:12][C:11]3[CH:16]=[C:17]([S:20]([N:23](CC4C=CC(OC)=CC=4)[C:24]4[S:25][CH:26]=[CH:27][N:28]=4)(=[O:22])=[O:21])[CH:18]=[CH:19][C:10]2=3)=[C:5]([O:38][CH3:39])[CH:4]=1)#[N:2].[Al].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][O:12][C:11]3[CH:16]=[C:17]([S:20]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)(=[O:21])=[O:22])[CH:18]=[CH:19][C:10]2=3)=[C:5]([O:38][CH3:39])[CH:4]=1)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3c2ccc(C#N)cc2OC)cc1
Agent: [Al]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1N1C(=O)COc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Yield: 22 %

Procedure:
Dissolved 4-(4-cyano-2-methoxyphenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (133 mg, 0.236 mmol) in 500 μl of DCM in a 10 mL rbf (wrapped with aluminum foil to exclude light) and added trifloroacetic acid (500 μl, 5.91 mmol). The solution was maintained at rt for 30 min until reaction was complete by LCMS. The reaction mixture was concentrated via rotary evaporation then purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% NHOH to give 4-(4-cyano-2-methoxyphenyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (23 mg, 0.052 mmol, 22% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3 H) 4.89 (s, 2 H) 6.39 (d, J=8.48 Hz, 1 H) 6.80 (d, J=4.47 Hz, 1 H) 7.23 (d, J=4.47 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.35-7.49 (m, 1 H) 7.53-7.66 (m, 2 H) 7.80 (s, 1 H). m/z ESI 441.0 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]1([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1>>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][C:24]([C:21]2([NH:20][C:16]([CH:9]3[CH2:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18])[CH2:22][CH2:23]2)=[CH:25][CH:26]=1)=[O:29]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC1(C)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)C3CC(C)(C)CCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 46.7 %

Procedure:
The title compound (D58) (250 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid (320 mg; described in J. Med. Chem. 1997, 40, 2491-2501) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (312 mg). Reaction time: 18 hrs
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=C[C:4]=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.C(S(Cl)(=O)=O)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([S:19]([N:51]1[CH2:52][CH2:53][N:48]([C:45]2[N:44]=[CH:43][C:42]([C:39]3[CH:40]=[C:41]4[C:33]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]6[CH:64]=[CH:65][CH:66]=[C:24]([F:23])[CH:25]=6)[CH:32]=5)=[CH:34][N:35]([S:54]([C:57]5[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=5)(=[O:56])=[O:55])[C:36]4=[N:37][CH:38]=3)=[CH:47][CH:46]=2)[CH2:49][CH2:50]1)(=[O:21])=[O:20])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: CCS(=O)(=O)Cl
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4S(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was alkylated with ethanesulfonyl chloride (25 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=700.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][N:4]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.4 g, 0.0356 mol), 1,1′,1″-(chloromethanetriyl)tribenzene (9.9 g, 0.0356 mol) and triethylamine (7.2 g, 0.0712 mol) were suspended in N,N-dimethylformamide (70.0 mL) and stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of water (30.0 mL) and extracted with ethyl acetate (3×30.0 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (40.0 mL), dried over sodium sulfate and concentrated in vacuo. This crude residue was initially purified via column chromatography eluting with petroleum ether:ethyl acetate (10:1, by volume) and then purified by preparative HPLC to yield title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[O:14][C:13]([CH2:15][CH2:16][C:17](Cl)=[O:18])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:17](=[O:18])[CH2:16][CH2:15][C:13]2[O:14][C:10]([CH3:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(CCC(=O)Cl)o1
Reactant: Nc1ccc(Br)cn1
Solvent: c1ccncc1
Product: Cc1ccc(CCC(=O)Nc2ccc(Br)cn2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-bromopyridin-2-amine (123a, 600 mg, 3.47 mmol) in pyridine (10 ml) was added 3-(5-Methyl-furan-2-yl)-propionyl chloride (718.3 mg, 4.16 mmol) and stirred at room temperature for 16 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-(5-Bromo-pyridin-2-yl)-3-(5-methyl-furan-2-yl)-propionamide (123): 1H NMR (500 MHz, DMSO) δ: 10.68 (s, 1H), 10.68 (s, 1H),8.42 (d, 1H), 8.07 (m, 1H), 5.94 (s, 1H), 5.92 (s, 1H), 2.85 (t, 2H), 2.70 (t, 2H), 2.19 (s, 3H). ESI-MS: 310.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>C(#N)C>[Br-:10].[CH:13]1[C:14]2[C:23](=[CH:22][C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[CH:25][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:4]=1
Reactant: BrCc1ccc2cc3ccccc3cc2c1
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2ccc3cc4ccccc4cc3c2)cn1Cc1ccc2ccccc2c1
Product: [Br-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)anthracene (2.71 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. 2-(Bromomethyl)naphthalene (2.21 g, 10.0 mmol) will be added to the filtrate and the mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure to yield the product.