Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2F)CC1
Yield: 94 %

Procedure:
Heat a mixture of 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 60 mg) and 2,4,6-trifluorobenzoyl chloride (59 mg) in 1,4-dioxane (5 mL) for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2M NH3 in methanol, evaporate and purify on a silica gel column (4 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give 94 mg of the title compound: mass spectrum (electric spray) m/z=396 (M+1); 1H NMR (CDCl3): 7.96 (m, 1H), 7.84 (br s, 1H), 7.05 (m, 1H), 6.79 (m, 3H), 3.48 (d, 1H), 3.16 (m, 3H), 2.91 (br d, 2H), 2.74 (s, 3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[CH:16][C:17](B2OC(C)(C)C(C)(C)O2)=[C:18]2[C:22]=1[C@H:21]([O:23][C:24]1[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=1)[CH2:20][CH2:19]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[C:17]1[CH:16]=[CH:15][C:14]([F:13])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:23][C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1)=[O:5]
Reactant: CN(C)C(=O)c1ccccc1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5ccccc5C(=O)N(C)C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 2-bromo-N,N-dimethylbenzamide and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.14 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[C:17](F)=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>CN(C)C=O>[Cl:8][C:9]1[C:17]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1F
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1-n1cccn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Pyrazole (210 mg, 3.09 mmol) was added to 190 mg (4.75 mmol) of 60 percent oil dispersed sodium hydride suspended in 7 mL of dry dimethylformamide. After the gas evolution had subsided, 500 mg (1.98 mmol) of 2-chloro-3-fluoro-4-methylsulfonylbenzoic acid was added and the mixture was stirred at 50° C. overnight. The mixture was then concentrated by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and extracted with dilute aqueous sodium bicarbonate solution. The aqueous extract was acidified with 1N aqueous hydrochloric acid and extracted with dichloromethane. The organic extract was concentrated by evaporation under reduced pressure. The crystalline residue obtained was purified by rinsing with ethyl acetate to obtain 540 mg (91 percent of theory) of the title compound as a white powder.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)=[O:18])=[O:14].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH2:54][C@@H:55]3[N:61]([CH:62]=2)[C:60](=[O:63])[C:59]2[CH:64]=[C:65]([O:91][CH3:92])[C:66]([O:68][CH2:69][CH2:70][CH2:71][O:72][C:73]4[C:88]([O:89][CH3:90])=[CH:87][C:76]5[C:77](=[O:86])[N:78]6[CH:84]=[C:83]([CH3:85])[CH2:82][C@H:79]6[CH:80]=[N:81][C:75]=5[CH:74]=4)=[CH:67][C:58]=2[N:57]=[CH:56]3)=[CH:49][CH:48]=1>CO.ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][C@@H:20]([CH3:24])[C:21]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH2:54][C@@H:55]3[N:61]([CH:62]=2)[C:60](=[O:63])[C:59]2[CH:64]=[C:65]([O:91][CH3:92])[C:66]([O:68][CH2:69][CH2:70][CH2:71][O:72][C:73]4[C:88]([O:89][CH3:90])=[CH:87][C:76]5[C:77](=[O:86])[N:78]6[CH:84]=[C:83]([CH3:85])[CH2:82][C@H:79]6[CH:80]=[N:81][C:75]=5[CH:74]=4)=[CH:67][C:58]=2[N:57]=[CH:56]3)=[CH:49][CH:48]=1)=[O:23])=[O:18])=[O:14]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](C)C(=O)O
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(C)=CN1C2=O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN5C(=O)C=CC5=O)C(C)C)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(C)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To a mixture of carboxylic acid 23 (8 mg, 21 umol) in 5% methanol/dichloromethane was added EEDQ (6.1 mg, 24.6 umol) and the mixture was stirred for 15 minutes under nitrogen at an ambient temperature. The resulting mixture was added to 11 (12 mg, 18.9 umol) and stirred for 3 hours under nitrogen. The reaction mixture was aspirated directly onto a 1 mm radial chromatotron plate and eluted with a gradient of 1 to 4% methanol in dichloromethane. Product containing fractions were concentrated under reduced pressure to give 9.4 mg (50%) of 30 as a yellow solid: MS (ES−) m/z 997.18 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11]CCC)[C:5]([OH:7])=[O:6].[C-]#N.[Na+].[C:18]([Cu])#[N:19]>CN(C=O)C>[C:18]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6])#[N:19]
Reactant: CCCOc1ccc(C(=O)O)cc1I
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)O)ccc1O
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of the product of Example 44 Step C (0.22 g; 0.72 mmol), NaCN (0.04 g; 0.8 mmol) and CuCN (0.07 g; 0.8 mmol) in anhydrous DMF (2 ml) was stirred at ˜110° C. for 2 h under N2. This was evaporated to dryness in vacuo and the residue was suspended in H2O (10 ml) and pH was adjusted to ˜10 with 1 M NaOH. The insoluble material was removed by filtration and the filtrate was acidified to pH˜3 with diluted HCl and the product was taken up by CH2Cl2 (2×20 ml). The organic phase was dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness under reduced pressure to give the title compound (0.1 g; 67%) as brownish solid. 1H-NMR (CDCl3) 1.06-1.14 (m, 3H); 1.85-1.97 (m, 2H); 4.1-4.18 (m, 2H); 7.02 (d, 1H, J=9 Hz); 8.24 (dd, 1H, J=3, 9 Hz); 8.31 (d, 1H, J=3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[CH2:23][O:22][C:21]3=[O:26])[CH2:14][CH2:13]1)=[N:7][CH:6]=[CH:5]2.[NH3:27]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH2:27])=[O:25])[CH2:14][CH2:13]1)=[N:7][CH:6]=[CH:5]2
Reactant: N
Reactant: O=C1COC(=O)N1CCC1CCN(c2nccc3cc(F)ccc23)CC1
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2nccc3cc(F)ccc23)CC1

Procedure:
The process is performed according to the procedure described in Example 3 (step 3.4). Starting with 0.597 g (1.67 mmol) of 3-{2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in Step 6.3, and 14.30 ml (100.20 mmol) of a solution (7M) of aqueous ammonia in methanol, and after chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by recrystallization from diisopropyl ether, 0.168 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](N)[N:14](C(OC(C)(C)C)=O)[CH2:15][C@H:16]([OH:26])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[CH2:5][CH3:6])[CH3:3].C[N:36](C=O)C>O1CCOCC1>[ClH:1].[CH2:2]([N:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH2:36])[CH2:15][C@H:16]([OH:26])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[CH2:5][CH3:6])[CH3:3]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccc(C(N)N(C[C@H](O)[C@@H](N)Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(CN(N)C[C@H](O)[C@@H](N)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
850 ml of a 4M solution of hydrogen chloride in dioxane is added to a solution of 57 g (124.8 mmol) of 1-[p-(N,N-diethylamino)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)-amino-5(S)-amino-6-phenyl-2-azahexane (Example 2d) in 200 ml of DMF and the whole is stirred at RT for 4 h. After that, the mixture is concentrated and treated firstly with dioxane and then with toluene with subsequent evaporation taking place in each case. The residue is triturated twice with dioxane and decanted off. The oily title compound which is obtained in this way is subjected to further processing without any additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:18])[CH3:17].C(N(CC)CC)C>>[CH2:16]([NH:18][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH3:17]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 74.2 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (800 mg, 2.75 mmol), ethylamine (4.13 mL, 8.26 mmol) and triethylamine(1.5 mL, 8.36 mmol) were reacted to form the desired product (610 mg, 74%). 1H NMR (MeOD-d4): δ 7.92 (d, 1H), 7.78 (d, 1H), 3.08 (q, 2H), 1.11 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4](C2C=CC(NC(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)=CC=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:39](C1C=CC=CC=1)[C:40]([O:42]C)=[O:41]>CN(C=O)C>[N:1]1([CH2:39][C:40]([OH:42])=[O:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CN1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of intermediate (10) (0.019 mol) and Na2CO3 (0.019 mol) in DMF (125 ml) was stirred at room temperature. Methyl 2-bromo-2-phenylacetate (0.01907 mol) was added dropwise. The mixture was stirred for 3 hours. The solvent was evaporated. The residue was taken up in water and DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0; 99.5/0.5) and separated by high performance liquid chromatography over Chiralpak AD (eluent: hexane/ethanol 70/30) in its enantiomers. The desired fractions were collected and the solvent was evaporated, yielding 1-piperidineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1A)-(intermediate 29, mp. 158° C., [α]D20=−28.86° (c=124.95 mg/5 ml in CH3OH)) after crystallisation from 2-propanol and 1-piperidineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, methyl ester, (α1B)-(intermediate 30, mp. 160° C., [α]D20=+27.69° (c=24.38 mg/5 ml in CH3OH)) after crystallisation from 2-propanol.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:4][N:3]=C1.[NH:32]1C=CN=N1.N1C=CN=C1>>[N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:5]=[CH:4][N:3]=[N:32]1
Reactant: c1c[nH]nn1
Reactant: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Agent: c1c[nH]cn1
Product: COc1cc(C(=O)c2c(-n3ccnn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
This material was prepared according to the procedure outlined above for 2-(N-imidazolyl)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (entry 27, Table 1), above, except the 1,2,3-triazole was used as the nucleophile in place of imidazole. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, 1H, J=1.21 Hz), 7.75 (d, 1H, J=1.20 Hz), 7.27 (d, 1H, J=8.60 Hz), 7.18 (d, 1H, J=8.66 Hz), 7.05 (s, 2H, benzoyl Hs), 3.94 (s, 3H, OMe), 3.74 (s, 6H, 2×OMe), 3.73 (s, 3H, OMe).
Reaction SMILES: N[C@H:2]([C:5]([OH:7])=O)[CH2:3][SeH].[CH2:8]([C:10]1[CH:15]=C[CH:13]=[CH:12][C:11]=1O)[CH3:9]>>[CH2:8]([C:10]1[C:15]2[O:7][CH:5]=[CH:2][C:3]=2[CH:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CCc1ccccc1O
Product: CCc1cccc2ccoc12

Procedure:
2h. 7-Ethyl-benzofuran is prepared by the method described in J.Chem.Sec. 1920, 1534, but using o-ethylphenol instead of o-cresol. The MS. of the product thus obtained shows the following ion peaks with the relative intensities given within brackets: 131 (100%), 146 (38%) and 77 (10%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([CH:11]3[CH2:15][CH2:14][CH:13]=[CH:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH2:16].C[N+]1([O-])CCOCC1.[OH2:25]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:12]3[OH:25])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O
Reactant: Nc1ncnc2c1nnn2C1C=CCC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)(C)O
Product: Nc1ncnc2c1nnn2[C@@H]1CC[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±)-7-Amino-3-(2-cyclopenten-1-yl)-1,2,3-triazolo[4,5-d]pyrimidine (4.80 g, 23.7 mmol), N-methylmorpholine N-oxide monohydrate (3.15 g, 26.1 mmol as 97%), water (35 ml), t-butylalcohol (175 ml) and 2.5% osmium tetroxide in t-butyl alcohol (1.0 ml) were refluxed for 3 hours and then stirred at 25° C. for 18 hours. The resulting mixture was evaporated to dryness and chromatographed on silica gel. Title compound was eluted with MeOH:CHCl3 /1:3 to give white crystals after two recrystallizations from ethanol-water (3.74 g, 67%); mp 244°-245° C.; 1H-NMR (Me2SO-d6) δ8.26 (s, 1, H-5'), 8.35 and 8.05 (both br s) overlapping 8.26 (s) (total 3 protons, tautomers NH2 and H-5'), 5.2-5.0 (m) overlapping 5.01 (d, J=7.3) (total 2, OH and H-3 ), 4.72 (d, J=3.5, 1, OH), 4.5-4.4 (m, 1, H-2), 4.1-4.0 (m, 1, H-1), 2.4-1.6 (m, 4, two CH2).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.N#N.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([CH3:33])[C:27]([CH3:34])=[N:26]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:33][C:28]1[C:27]([CH3:34])=[N:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([NH:22][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:24]=2)[N:29]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ccc(N)cc2nc1C
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)c(C)nc3c2)cc1
Yield: 89.9 %

Procedure:
To a solution of 0.4n-propylbenzenesulphonyl chloride (106 mg, 0.485 mmol) in dichloromethane (3 mL) was added pyridine (90 μL, 1.2 mmol) and the mixture was stirred under. N2 for 5 min, after which time 6-amino-2,3-dimethylquinoxaline (80 mg, 0.46 mmol) was added. The resulting mixture was stirred for 6 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (147 mg, 90%), single spot at Rf 0.69 (ethyl acetate). mp 198.4-198.8° C., HPLC purity 99+% (tR 2.39 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.86 (1H, d, J=8.9 Hz), 7.72 (2H, d, Jz;8.4 Hz), 7.56 (1H, d, J=2.5 Hz), 7.48 (1H, dd, J9.2, 2.5 Hz), 7.20 (2H, d, J=7.9 Hz), 6.82 (1H, s, N—H, 2.67 (6H, s), 2.56 (2H, t, J=7.5 Hz), 1.57 (2H, sextet, J=7.4 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 354.31 (M−). FAB-MS (MH+, C19H21N3O2S): calcd 356.1432, found 356.1433.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[F:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)c1cc(C(C)(C)C)c(F)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,3,5-tri-tert-butylbenzene (442 mg, 2.0 mmol) in ACN (20 mL) was cooled to 0° C. under N2. Selectfluor (1.06 g, 3.0 mmol) was added, keeping the temperature close to 0° C. The reaction was stirred overnight warming up to rt, poured into aq. Na2CO3 (15 mL) and extracted with Et2O (30 mL). The organic layer was washed with brine, dried with Na2SO4, filtered and evaporated to give compound P31a (430 mg, 81%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:16])[CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[S:27](=[O:30])(=[O:29])[NH2:28].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([N:12]1[C:11]2[CH:10]=[C:9]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[C:19]([S:27]([NH2:28])(=[O:29])=[O:30])[CH:20]=3)=[O:23])[CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:16])[CH3:15]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CC(=O)n1c2ccccc2c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)n1c2ccccc2c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 1-carbazol-9-yl-ethanone and 2.43 g of 4-chloro-3-sulfamoyl-benzoyl chloride in methylene chloride (20 mL) is added 2.55 g of aluminum chloride. The mixture is stirred at 50° C. overnight. The solution is then cooled at −78° C., quenched with a 6 N HCl solution and allowed to warm up to room temperature. Methylene chloride is added to dissolve the precipitate and the solution is extracted, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to afford 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as yellow foam. MS (m/z): 427 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10→100% CH3CN in 5 min) room temperature=5.35 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:13])[CH2:14][C:15]([N:17]([CH3:25])[C:18]2[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)CC(CCO)c1ccc(F)c(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
3,4-Difluoro-β-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (4.3 g) in EtOAc (100 mL) was treated with carbonyldiimidazole (3.24 g) and N,N-dimethylaminopyridine (195 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (3.02 g) in H2O (50 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (1×100 mL), sat. NaHCO3 (1×100 mL) and water (1×100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (3.64 g). Mass spectrum (CI): 320.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:13](OCC)=[O:14].C[O-].[Na+].Cl>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[S:10][CH2:9][C:8](=[CH:13][OH:14])[C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: O=C1CCSc2c(Cl)cccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1C(=CO)CSc2c(Cl)cccc21
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
A solution of 8-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one (10 g) in benzene (125 ml) was added dropwise to a mixture of ethyl formate (7.46 g) and sodium methoxide (5.44 g) in benzene (40 ml) with ice cooling and stirring over a period of 10 minutes. After being stirred for 1 hour at room temperature, 10% hydrochloric acid was added to the reaction mixture. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-chloro-2,3-dihydro-3-hydroxymethylene-4H-1-benzothiopyran-4-one (10.13 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:13][N:14]2[CH3:17])=[CH:10][C:9]=1[O:37][CH3:38].Br[CH:40]([CH3:42])[CH3:41]>CN(C)C=O.O>[CH:40]([O:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:13][N:14]2[CH3:17])=[CH:10][C:9]=1[O:37][CH3:38])([CH3:42])[CH3:41]
Reactant: CC(C)Br
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (70 mg) was added to a solution of 2-(6-hydroxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [112 mg, Reference Example 83] in dry dimethylformamide (5 mL) under an argon atmosphere at ambient temperature. The mixture was allowed to stir for 10 minutes then treated with 2-bromopropane (66 μl) and heated at 70° C. for 3 hours. Additional portions of potassium carbonate (70 mg) and 2-bromopropane (66 μl) were then added and the mixture was stirred and heated at 70° C. for 4 hours. The cooled reaction mixture was poured in water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with brine (20 mL), then dried over magnesium sulfate and then evaporated. The brown residue was subjected to flash column chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (3:2, v/v) to give the title compound (56 mg) as an off-white foam. TLC: RF=0.47 (cyclohexane/ethyl acetate, 1/1). MS: CI (NH3); m/z=490 MH+.