Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1.C(O)C.O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4ccc(Cl)cc4[nH]3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Stir, at room temperature, a mixture of 345 mg of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E) in a mixture of 2 ml of acetic acid, 2 ml of ethanol and 2 ml of water in the presence of 65 mg of powdered zinc. After 1 hour and 3 hours, add, each time, a further 65 mg of powdered zinc and maintain the stirring for approximately 4 hours. Add Celite, filter over sintered glass and wash the precipitate with 200 ml of a mixture of methanol and dichloromethane (20/80 by volume). The filtrate is evaporated to dryness under vacuum, add twice 50 ml of toluene and re-evaporate, each time, to dryness under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of dichloromethane-7N solution of ammonia in methanol (90/10 by volume). In this way, we obtain 275 mg of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine in the form of a beige foam with the following characteristics:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51]2[CH:60]=[CH:59][N:58]=[C:57]3[C:52]=2[C:53]2[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=2[C:55](=[O:61])[NH:56]3)[CH2:46][CH2:45]1>CN(C=O)C>[C:1]1([CH2:7][C:8]([N:44]2[CH2:45][CH2:46][CH:47]([NH:50][C:51]3[CH:60]=[CH:59][N:58]=[C:57]4[C:52]=3[C:53]3[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=3[C:55](=[O:61])[NH:56]4)[CH2:48][CH2:49]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Reactant: O=C(O)Cc1ccccc1
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: CN(C)C=O
Product: O=C(Cc1ccccc1)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
Phenylacetic acid (10 mg, 0.07 mmol), DIEA (28 mg, 0.22 mmol), and HATU (28 mg, 0.07 mmol) were dissolved in DMF (1 mL), and stirred for 30 min at room temperature. 358 (17 mg, 0.06 mmol) was added, and the reaction mixture was stirred for another 1 h at room temperature. The crude material was purified directly via HPLC to provide 360 (10 mg, 30% yield) as a solid. LC-MS (M+H=413, obsd.=413).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:10]([OH:12])=[O:11].[CH:13]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[CH3:13][O:11][C:10]([C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:2]1[NH2:1])=[O:12]
Reactant: c1ccccc1
Reactant: N[C@H]1CCCCCC[C@H]1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
cis-2-Amino-cyclooctanecarboxylic acid (0.65 g, 3.8 mmol) was dissolved in methanol (5 mL). Benzene (7.5 mL) was added followed by dropwise addition of a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (3.5 mL). The yellow solution was stirred at 25° C. for 45 min. The solution was concentrated in vacuo. The residue was dissolved in methanol (20 mL) and concentrated in vacuo to afford the desired product, cis-2-amino-cyclooctanecarboxylic acid methyl ester (0.66 g, 3.56 mmol, 94%), as a colorless oil. LC-MS (ESI) calcd for C10H19NO2 185.14, found 186.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([CH3:16])[CH2:6]2.O.O.Cl[Sn]Cl.C(Cl)Cl.[OH-].[Na+]>C(O)C.O>[NH2:12][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH3:16])[C:8]2=[O:15])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)C2
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1N)C(=O)N(C)C2
Temperature: 65 °C
Yield: 97.3 %

Procedure:
To crude 5-methoxy-2-methyl-6-nitroisoindolin-1-one (121 mg, 0.54 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (487 mg, 2.16 mmol) and the mixture was heated to 65° C. for 24 h. DCM (10 mL) and 2M NaOH(aq) (10 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give impure 6-amino-5-methoxy-2-methylisoindolin-1-one (101 mg, 97%) as an off-white solid. The crude material was used directly in the next reaction without any further purification. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=193 at 2.00 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1SC(C(O)=O)=C[CH:9]=1)=[O:4].O[N:14]1C2C=CC=CC=2N=N1.[ClH:23].C[N:25](C)[CH2:26][CH2:27][CH2:28][N:29]=[C:30]=[N:31]CC.CN1CCOCC1.C(NC(NC(OC(C)(C)C)=O)=NCCN)(OC(C)(C)C)=O>CN(C=O)C>[ClH:23].[ClH:23].[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH:31][C:30]1[N:25]=[CH:26][CH:27]=[CH:28][N:29]=1)[CH2:9][NH2:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1ccc(C(=O)O)s1
Agent: CC(C)(C)OC(=O)NC(=NCCN)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(CN)Nc1ncccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Now referring to Scheme K, to Compound XXIII: thiophene-2,5-dicarboxylic acid monomethyl ester (923 mg, 4.96 mmol) in DMF (10 ml) was added 1-hydroxybenzotriazole (HOBT) (870 mg, 6.45 mmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrocloride (EDC) (1.23 g, 6.45 mmol) and (1.2 ml, 10.9 mmol) of NMM. Compound XXIV: N,N′-Bis-(Boc)-N″-(2-Amino-ethyl)-guanidine (6.45 mmol, 1.96 g) was then added in DMF(10 ml) to the reaction mixture which was then left to stir at room temperature for 16 hours. Solvent was evaporated and the residue was thrown in a 10% citric acid solution (50 ml) and extracted with ETOAC (3×70 ml). The organic phases were combined and washed with a saturated solution of NaHCO3 followed by a solution of Brine, dried over MgSO4 and evaporated. The crude residue was then purified by flash column chromatography using CH2Cl2/MeOH (10:0.2) to give the desired product (Compound XXVII) in 94% yield. 1H NMR (CDCl3, 400 MHz) δ 1.1-1.34 (m, 21H), 3.41-3.81 (m, 4H), 3.88 (s, 3H), 5.58-5.59 (d, 1H), 7.69-7.70 (d, 1H), 8.43-8.54 (broad s, 1H), 8.70-8.88 (m, 1H).
Reaction SMILES: [OH:1][C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:26]3[O:25][CH2:29][CH2:28][O:27]3)=[CH:43][CH:42]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: O=Cc1ccc(OCCCCCC2OCCO2)cc1
Reactant: O=C(OCC1CCNCC1)C(O)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCC1CCN(Cc2ccc(OCCCCCC3OCCO3)cc2)CC1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirred solution of piperidin-4-ylmethyl 2-hydroxy-2,2-diphenylacetate (0.4 g, 1.23 mmol) and 4-((5-(1,3-dioxolan-2-yl)pentyl)oxy)benzaldehyde (0.38 g, 1.44 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (0.388 g, 1.83 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc and saturated sodium hydrogen carbonate. The organic phase was dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1 to 10% methanol in ethyl acetate to afford the title compound as a colourless oil (0.50 g, 26%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25](O)=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O>[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[NH:1][C:2]2[C:3]([C:4]([NH2:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: O=C(O)c1cnccn1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2nc(-c3cnccn3)[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A solution of 1.68 g (7.5 mmol) of 2,3-diaminobenzamide and 3.04 g (30 mmol) of triethylamine in 50 ml of dimethylformamide was stirred at room temperature for 1 hour. 0.93 g (7.5 mmol) of pyrazine-2-carboxylic acid and 1.01 g (7.5 mmol) of N-hydroxybenzotriazole (HOBt) were added. After stirring at room temp. for 15 minutes, the mixture was cooled to 0° C. 1.44 g (7.5 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) were added, and the mixture was stirred at room temp. for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate. The residue obtained after concentration in vacuo was taken up in 50 ml of glacial acetic acid and refluxed for 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was stirred in diethyl ether. The precipitate was removed by filtration and dried at 40° C. in vacuo. 1.11 g of brown crystals were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([Cl:11])=[N:9][CH:10]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:19](C1(C)C=CC=C[C@]1(C)S([O-])(=O)=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH:38]1C[CH2:41][CH2:40][CH2:39]1>CO>[C:19]([N:38]1[CH2:39][CH2:40][CH2:41][C@H:2]1[CH2:1][O:4][C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]([CH3:12])[CH:6]=1)([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)C1(C)C=CC=C[C@]1(C)S(=O)(=O)[O-]
Reactant: CC(=O)Oc1cnc(Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46.2 %

Procedure:
To a solution of 5-acetoxy-2-chloro-3-methylpyridine (1.80 g, 8.9 mmol) in MeOH (5 mL) was added potassium carbonate (1.4 g, 10.1 mmol). The reaction mixture was allowed to stir at room temperature for 2.5 h. Solvent was evaporated. The residue was then dissolved in DMF, and 1-BOC-2-(S)-methyltoluenesulfonate-pyrrolidine (2.0 g, 5.63 mmol) from a above was added. The reaction mixture was stirred at 60° C. for 16 h. Solvent was evaporated. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 3:1) to afford an oil (850 mg, 30%): 1H NMR δ 1.47 (s, 9H), 1.80-2.00 (m, 2H), 2.00-2.08 (m, 2H), 2.34 (s, 3H), 3.24-3.44 (m, 2H), 3.92 (m, 1H), 4.02-4.20 (m, 2H), 7.16 (m, 1H), 7.92 (d, 1H, J=2.5 Hz); MS (CI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: BrCCCCc1c[nH]c2ccccc12
Product: Cl
Product: Clc1cccc(N2CCN(CCCCc3c[nH]c4ccccc34)CC2)c1Cl

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 3-(4-bromobutyl)-1H-indole. Mp 121–122° C. 1H NMR (DMSO-d6): 1.45–1.55 (m, 2H); 1.65–1.75 (m, 2H); 2.35 (t, 2H); 2.50 (b s, 4H); 2.70 (t, 2H); 2.95 (b s, 4H); 6.95 (t, 1H); 7.05 (t, 1H); 7.10–7.15 (m, 2H); 7.25–7.30 (m, 2H); 7.35 (d, 1H); 7.50 (d, 1H); 10.75 (b s, 1H). Ms m/z: 402 (MH+).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)(=O)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([NH:40][CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[CH:14]=[N:15][C:9]=3[CH:8]=2)[CH2:39][CH2:38]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: NC1CC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cc(CNC4CC4)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 289 mg of crude [3-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (example 49, step 1) and 0.35 ml cyclopropylamine in 7 ml dichloromethane yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6].[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[Si:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC/C=C/c1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
3-Hydroxy-5-[(1E)-3-methoxyprop-1-en-1-yl]benzaldehyde (1 eq.) from the previous step and tert-butylchlorodimethylsilane (1 eq.) were combined in DMF (0.5 M). To this solution was then added imidazole (1.5 eq.), and the reaction mixture was stirred at rt for 16 h. The resulting solution was quenched with water and extracted with ether/hexanes (1:1 v/v). The combined organic extracts were washed with brine, dried over MgSO4, and filtered through a plug of SiO2. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[N:21]([C@H:24]1[C@H:31]2[C@H:27]([CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:30]2)[CH2:26][CH2:25]1)=[N+]=[N-]>O1CCCC1>[CH2:32]([N:29]1[CH2:30][C@H:31]2[C@H:24]([NH2:21])[CH2:25][CH2:26][C@H:27]2[CH2:28]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 80 °C

Procedure:
Triphenylphosphine (4.49 g, 17.13 mmol) and water (1.234 mL, 68.5 mmol) were added successively to a mixture of (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole (1.384 g, 5.71 mmol) in tetrahydrofuran (30 mL). The reaction was refluxed at 80° C. for 2 hours. The crude material was adsorbed onto silica gel and applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-40) and eluted with 1-10% methanol (2 N ammonia)/chloroform to give (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.45 (d, J=7.4, 2H), 7.38 (t, J=7.5, 2H), 7.29 (t, J=7.3, 1H), 3.52 (s, 2H), 3.14 (dd, J=5.7, 10.7, 1H), 2.62-2.55 (m, 1H), 2.52 (dd, J=3.2, 9.0, 1H), 2.38-2.29 (m, 3H), 2.20-2.13 (m, 1H), 2.01-1.84 (m, 2H), 1.40-1.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH:38]1([C:42](=[S:44])[NH2:43])[CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:44][C:42]([CH:38]3[CH2:41][CH2:40][CH2:39]3)=[N:43][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Reactant: NC(=S)C1CCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Yield: 30.7 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (1.34 g, 3.03 mmol), NBS (0.540 g, 3.03 mmol), cyclobutanecarbothioamide (0.349 g, 3.03 mmol) the title compound of Step A was obtained (0.5 g, 0.931 mmol, 30.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.52 (d, J=5.3 Hz, 1H), 7.58-7.33 (m, 6H), 7.28 (t, J=7.9 Hz, 1H), 6.83 (d, J=5.3 Hz, 1H), 3.89 (quin, J=8.6 Hz, 1H), 2.43-2.19 (m, 4H), 2.08-1.92 (m, 1H), 1.92-1.78 (m, 1H). MS (ESI): 537 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].C[C:15]([O:17][C:18](C)=O)=O.C(OC)(OC)OC>CN(C)C=O>[CH3:1][N:2]1[C:11](=[O:12])/[C:10](=[CH:15]/[O:17][CH3:18])/[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)Cc2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: CO/C=C1/C(=O)N(C)C(=O)c2ccccc21
Temperature: 125 °C

Procedure:
To a stirred mixture of 0.35 g (2.0 mmol) of (N-methyl)isoquinoline-1,3(2H,4H)-dione, 3.2 ml of Ac2O, and 0.80 ml of N,N-DIMETHYLFORMAMIDE (DMF) is added 0.44 ml (4.0 mmol) of (MeO)3CH at 25° C. The mixture is stirred at 125° C. for 30 m, cooled, and concentrated under high vacuum. The residue is recrystallized from Et2O-hexane to give 0.20 g of tan solid, mp 145-150° C. (dec); MS (ES+) m/z 218.2 (M+H)+1.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:20][O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1
Reactant: CCOC(=O)n1nc(O)c2ccc(C(=O)OC)cc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)n1nc(OC)c2ccc(C(=O)OC)cc21

Procedure:
1-Ethyl 6-methyl 3-hydroxy-1H-indazole-1,6-dicarboxylate (1.35 g, 5.11 mmol) was suspended in acetone (65 mL). Cesium carbonate (1.75 g, 5.36 mmol) and methyl iodide (1.0 mL, 15 mmol) were added and the reaction was heated to reflux for 23 hours. The reaction was concentrated to dryness. The residue was taken up in dichloromethane (100 mL) and water (100 mL). The layers were separated and the aqueous was extracted again with dichloromethane. The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography gave two regioisomeric products.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH3:24])([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].[CH2:27](I)[CH3:28].O.O.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>O.C(O)(C)C.CN(C)C=O>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[CH2:27]([O:13][C:10]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH3:24])[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)[CH3:28]
Reactant: [H][H]
Reactant: CCI
Reactant: CCOc1ccccc1OCC1(O)CCN(Cc2ccccc2)C1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCOc1ccccc1OCC1(OCC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride, 3.44 g (0.0816 mole) in 57% mineral oil suspension was washed three times with petroleum ether (30°-60° C.) under nitrogen atmosphere, suspended in 60 ml of freshly distilled anhydrous dimethylformamide and treated slowly with a solution of 24.3 g (0.0742 mole) of 1-benzyl-3-(2-ethoxyphenoxy)methyl-3-pyrrolidinol in 60 ml of freshly distilled anhydrous dimethylformamide. After hydrogen evolution had ceased, a solution of 11.6 g (0.0742 mole) of ethyl iodide in 60 ml of freshly distilled anhydrous dimethylformamide was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours (overnight), then cautiously diluted with 50 ml of water and poured into 1500 ml of water. The suspension was extracted with chloroform (3×200 ml) and the combined chloroform extracts washed with water (3×200 ml), dried over magnesium sulfate and evaporated under reduced pressure (26.1 g). The crude product which contained starting material was dissolved in benzene and chromatographed on a 500 g column of florisil packed in benzene. The column was eluted with benzene and methanol-benzene solvent mixtures. The fractions containing product were combined and evaporated under reduced pressure. Weight of residue was 15.0 g (57%). A mixture of 3.0 g (0.0084 mole) of the product and 1.06 g (0.0084 mole) of oxalic acid dihydrate in isopropanol was warmed to solution, filtered, and the filtrate seeded. The oxalate salt, 3.4 g, was collected by filtration, m.p. 125°-127° C. The material was recrystallized twice from isopropanol-isopropyl ether leaving 0.8 g of salt, m.p. 127°-129° C., which did not analyze as expected. The filtrate gave a second crop, 1.0 g, m.p. 125°-127° C. which was dried at 62° C. and 0.01 mm pressure for 4 hours and at room temperature and 0.01 mm pressure overnight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=[CH:6][C:5]2=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]2[NH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[C:8]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH:9]=3
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
6-Bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid (758 mg, 1.707 mmol, Example 58D) was mixed with morpholine (892 mg, 10.24 mmol), HATU (1947 mg, 5.12 mmol) and DMAP (625 mg, 5.12 mmol) in DMF (8 mL) and stirred for 2 hrs at r.t. The mixture was added slowly to 200 ml H2O while stirring. Resulting mixture was stirred for 10 mins. The resulting yellow precipitate was filtered and air-dried overnight with air-suction to give 546 mg of 3-bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide which was used as such in the next step.