Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12]1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1.ClCCl.C(O)C.N.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12]1)[C:5]([NH:61][C@H:59]([C:57]1[NH:56][C:55]2[CH:62]=[CH:63][C:52]([Cl:51])=[CH:53][C:54]=2[N:58]=1)[CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(-n2ccc3c2CCCC3)c(Cl)c1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(-n2ccc3c2CCCC3)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 25 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(4,5,6,7-tetrahydroindol-1-yl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 25%; Rf value: 0.90 (silica gel: dichloromethane/ethanol/ammonia=4:1:0.1); C24H22C12N4O (453.371); mass spectrum: (M+H)+=453/455/457 (chlorine isotope).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([CH:79]=O)=[CH:75][CH:74]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:76]3[CH:77]=[CH:78][C:73]([O:72][CH3:71])=[CH:74][CH:75]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(C(F)(F)F)nc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(C(F)(F)F)nc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 42.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.043 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.13 mmol, 0.13 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.048 mmol, 6.5 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 52%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.64 (s, br, 4H, piperazine N(CH2)2), 3.67 (s, br, 4H, piperazine N(CH2)2), 3.73 (s, 2H, NCH2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.8 Hz, 2H, methoxyphenyl H-2 & H-6), 7.91 (d, br, J=7.6 Hz, 1H, pyridine H-5), 8.09 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.13 (d, J=8.7 Hz, 2H, methoxyphenyl H-3 & H-5), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.77 (s, br, 1H, pyridine H-2), 13.58 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[CH:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:16])[C:10]=3[Cl:15])[NH:5][C:4]=2[C:3]1=[O:17].[Li+].[Br-]>CN(C=O)C>[Cl:15][C:10]1[C:9]([Cl:16])=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12]1[CH:13]=[CH:14][CH:2]=[C:3]([OH:17])[C:4]=1[NH:5]2
Reactant: O=C1c2[nH]c3ccc(Cl)c(Cl)c3c2CCC1Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1cccc2c1[nH]c1ccc(Cl)c(Cl)c12
Temperature: 150 °C

Procedure:
2-Bromo-5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.33 mmol) was dissolved in anhydrous DMF (4 mL) and LiBr (0.031 g, 0.35 mmol) followed by Li2CO3 (26 mg, 0.35 mmol) were added. The reaction mixture was heated to 150° C. for 30 min, then cooled to room temperature, poured into ice water and extracted with EtOAc (3×20 mL). The combined organic extracts were concentrated in vacuo to obtain the crude compound which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to give the title compound as an ash solid (0.04 g, 40%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.38 (bs, 1H), 8.20 (d, J=9.0 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H), 7.16 (m, 1H), 6.91 (d, J=8.0 Hz, 1H), 5.10 (bs, 1H).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:43])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:25][C:26]2[C:31]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:29]=[C:28](Cl)[N:27]=2)[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[CH:8][CH:7]=1.[CH2:44]([OH:48])[CH:45]([CH3:47])[CH3:46]>C1COCC1.CC(O)=O.O>[CH2:32]([C:31]1[C:26]([CH2:25][N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:4])=[O:43])=[CH:7][CH:8]=2)[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[N:27][C:28]([O:48][CH2:44][CH:45]([CH3:47])[CH3:46])=[N:29][C:30]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1c(CN(Cc2ccc(C(=O)OC)cc2)Cc2ccc3c(c2)OCCO3)nc(Cl)nc1-c1ccccc1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCc1c(CN(Cc2ccc(C(=O)O)cc2)Cc2ccc3c(c2)OCCO3)nc(OCC(C)C)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (60% dispersion in mineral oil) (40 mg) is added to a solution of 4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (46 mg, 0.0804 mmol) in THF (3 mL) containing isobutyl alcohol (0.5 mL) at room temperature. The mixture is stirred at room temperature for 5 minutes and then at reflux for 2 hours. Next, H2O (0.5 mL) is added and heating is continued for an additional 30 minutes. After cooling to room temperature, the reaction mixture is treated with a few drops of AcOH until pH 4–5. The mixture is then diluted with H2O and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by preparative TLC, eluting with 20:1 CHCl3-MeOH. The band containing the product affords 28.4 mg 4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid as a colorless gum. 1H NMR (CDCl3, 300 MHz) δ 8.02 (br, 2H), 7.39 (br, 7H), 6.87 (br s, 1H), 6.78 (br s, 2H), 4.21 (br s, 4H), 4.12 (br d, J=6.3 Hz, 2H), 3.70 (br, 4H), 3.54 (br s, 2H), 2.54 (br m, 2H), 2.13 (br, 1H), 1.02 (d, J=6.3 Hz, 6H), 0.94 (br 4H), 0.60 (br, 3H) ppm. MS: m/z 596 [M+1].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:22]([F:24])[F:23])=[N:8][N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5])C.[OH-].[Na+]>C(O)C>[C:18]([N:9]1[C:10]([C:11]([F:17])([F:16])[C:12]([F:13])([F:14])[F:15])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:22]([F:24])[F:23])=[N:8]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1c(C(F)F)nn(C(C)(C)C)c1C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1nc(C(F)F)c(C(=O)O)c1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
N-tert-Butyl-3-difluoromethyl-5-pentafluoroethyl-4-pyrazolecarboxylic acid ethyl ester (2.0 g, 5.50 mmol) in ethanol (10 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (2.0 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (40 ml) and extracted with diethyl ether (20 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×30 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-tert-Butyl-3-difluoromethyl-5-pentafluoroethyl-4-pyrazolecarboxylic acid (1.83 g, 5.44 mmol, 99%) was isolated as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31][C:32](C2C=CC=CC=2)([C:39]2C=CC=CC=2)C2C=CC=CC=2)[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:55])[CH3:54])[NH:10][C:9]1=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=[O:65].C([C@H]1NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCS)OC(=O)CNC(=O)[C@@H](C(C)C)NC1=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(Cl)(C)=O>C(Cl)Cl>[CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31][C:32](=[O:65])[CH3:39])[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:54])[CH3:55])[NH:10][C:9]1=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCS)OC(=O)CNC1=O
Agent: CC[SiH](CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)SCC/C=C/[C@@H]1CC(=O)N[C@H](C)C(=O)N[C@H](Cc2ccccc2)C(=O)N[C@H](C(C)C)C(=O)NCC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a stirred solution of 15 (15 mg, 19 μmol) in CH2Cl2 (0.8 mL) was added Et3SiH (16 μL, 0.1 mmol) and TFA (0.2 mL). After stirring at room temperature for 30 minutes under an inert atmosphere, the reaction mixture was concentrated and the residue dried by high vacuum. Without further purification, the crude thiol 16 was used in next step. At 0° C., to a stirred solution of thiol 16 in CH2Cl2 (0.3 mL) was added DIPEA (17 μL, 0.1 mmol) and AcCl (2 μL, 28 □mol). After 30 minutes the reaction mixture was warmed to rt and stirred for a further 1.5 h, whereupon it was quenched by addition of 1M HCl (1 mL). EtOAc (5 mL) was added to dilute the solution, phases separated, and the aqueous phase extracted with EtOAc (2×1 mL). The combined organic phases were washed with sat. aq NaCl (2 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent: 1-10% IPA/CH2Cl2) to give compound 17 (5 mg, 8 μmol, 45%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[CH:18]=1)[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[C:18]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: CCc1cc2cc(Cl)ccc2o1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1oc2ccc(Cl)cc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 7.06 g 2-ethyl-5-chlorobenzo[b]furan in the presence of 11.4 g aluminum chloride. Colorless crystals, m.p. 130°-133° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=[N+:2]=[N-:3].[C:38]([C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1)#[CH:39].[Na+].[Cl-]>CC(O)(C)C.O>[N:35]1[CH:34]=[CH:33][C:32]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N:1]4[CH:39]=[C:38]([C@@H:40]5[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]5)[N:3]=[N:2]4)[CH:5]=3)[N:9]([C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:37][CH:36]=1
Reactant: C#C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2cn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
5-azido-3-(pyridin-4-yl)-1-trityl-1H-indazole (1.0 g, 2.1 mmol) and (S)-tert-butyl 3-ethynylpiperidine-1-carboxylate (0.43 g, 2.1 mmol) were suspended in t-BuOH:H2O (1:1 10 mL:10 mL) and then CuSO4.5H2O (5 mg, 0.002 mmol) and Na-Ascorbic acid (40 mg, 0.21 mmol) were added sequentially. Reaction mixture was stirred vigorously at room temperature overnight. After the completion of reaction, added sat. NaCl (30 mL), extracted with EtOAc (3×50 mL), evaporated the organic solvent to give (R)-tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (1.26 g) which was used for next step with out purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=O)=O.[C:39](#[N:45])[CH2:40][CH2:41][CH2:42][C:43]#[CH:44].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[Cu](I)I>[C:39]([CH2:40][CH2:41][CH2:42][C:43]#[C:44][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:11]([CH2:21][NH:22][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)#[N:45]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OS(=O)(=O)C(F)(F)F)cc23)cc1
Reactant: C#CCCCC#N
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#CCCCC#N)cc23)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (3.03 g, 6.13 mmol), copper iodide (176 mg, 0.920 mmol) and hex-5-ynenitrile (2.86 g, 30.7 mmol) in tetrahydrofuran (30 ml)-triethylamine (10 ml) was added dichlorobistriphenylphosphinepalladium (431 mg, 0.613 mmol), and the mixture was stirred under an argon atmosphere at 80° C. for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give black crystals. The crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, yield 84%) as white crystals. Subsequently, tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, 5.17 mmol) and 10% palladium-carbon (550 mg) were suspended in a mixed solvent of ethanol (200 ml)-tetrahydrofuran (35 ml) and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl {[6-(5-cyanopentyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.37 g, yield 92%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (81) and benzyl bromide according to General Procedure B. Yield 391 mg (47%), MP 119° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.92 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.54 (s, 2H), 6.65 (dd, J=1.6, 3.2, Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.20 (m, 5H), 7.87 (d, J=3.2 Hz, 1H), 8.18 (dd, J=2.8, 8.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 505 (M+1). Anal. (C27H25FN4O5) C, H, N.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16]C(=O)C(F)(F)F)[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>O.C(#N)C>[NH2:16][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[C:8]([S:10]([F:15])([F:11])([F:12])([F:13])[F:14])[CH:7]=1
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
N-(3-Acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (4 g, for preparation see example 4d) was suspended in 6 ml of water and 12 ml of acetonitrile, and 6 ml of concentrated sulfuric acid were added dropwise to this suspension. After stirring at 75° C. for 4 h and leaving to stand at RT overnight, the reaction was completed by adding another 2 ml of concentrated sulfuric acid and heating the mixture at 75° C. for 3 h. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The ethyl acetate phase was washed to neutrality with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of chromatography on silica gel. The product-containing fractions were combined and the solvent (heptane/ethyl acetate) was concentrated under reduced pressure. 2.53 g of 1-[3-amino-5-(pentafluorosulfanyl)phenyl]ethanone were obtained.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[CH:4][CH:3]=1.[Br-].[CH3:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[Zn+].[NH4+].[Cl-]>C1COCC1>[CH2:18]([CH:17]([C:16]1[C:11]2[N:12]([C:8]([C:5]3[N:6]([CH3:7])[C:2]([C:27]4[S:28][CH:29]=[CH:30][C:26]=4[CH3:25])=[CH:3][CH:4]=3)=[C:9]([CH3:23])[N:10]=2)[N:13]=[C:14]([CH3:22])[CH:15]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: Cc1ccsc1[Zn+]
Reactant: CCC(CC)c1cc(C)nn2c(-c3ccc(Br)n3C)c(C)nc12
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3ccc(-c4sccc4C)n3C)c(C)nc12
Temperature: 60 °C
Yield: 55.4 %

Procedure:
A THF slurry (5 mL) of 3-(5-bromo-1-methyl-1H-pyrrol-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (143 mg, 0.38 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 19 mg, 0.023 mmol) is treated with 3-methyl-2-thienyl zinc bromide (Aldrich, 0.5 M in THF, 3.8 mL, 1.9 mmol) then heated to 60° C. for 1 hr. The resulting mixture is poured into sat'd NH4Cl (25 mL) and extracted with diethyl ether (35 mL). The organic extract is washed with aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 15% ethyl acetate in hexane) to elute the product. The material is purified a second time by flash chromatography using hexane-ethyl acetate gradient (100% hexane to 12% ethyl acetate in hexane) to elute the product. Only the fractions containing pure desired product, as judged by MS analysis, are collected and give the title compound (82.6 mg, 55% yield) as an oil. ES-MS (m/z): calc'd for C23H28N4S: 392.20. found 393.1 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.28 (d, J=5.3 Hz, 1H), 6.96 (d, J=4.8 Hz, 1H), 6.67 (br s, 1H), 6.39 (d, J=3.5 Hz, 1H), 6.37 (d, J=4.0 Hz, 1H), 3.35 (br s, 1H), 3.33, (s, 3H), 2.52 (s, 3H), 2.51 (s, 3H), 2.26 (s, 3H), 1.89-1.76 (m, 4H), 0.87 (t, J=7.5 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:12])=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(I)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
2-Amino-benzenesulfonamide (5.15 g, 29.3 mmol) was dissolved in chloroform (87 mL), and N-iodosuccinimide (7.29 g, 30.77 mmol) was added under a nitrogen atmosphere. The mixture was heated at reflux for 24 h, allowed to cool to 25° C., and filtered through a sinter funnel. The solid was washed with chloroform and 10% methanol/chloroform (3-8 times) to afford the desired product, 2-amino-5-iodo-benzenesulfonamide (6.78 g, 22.75 mmol, 78% yield) as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6): 5.98 (s, 2H), 6.62 (d, 1H, J=8.8 Hz), 7.31 (s, 2H), 7.45 (dd, 1H, J=8.8, 2.4 Hz), 7.73 (d, 1H, J=2.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]2=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=2)[CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[N:53]1([C:56]2[CH:57]=[CH:58][C:59]([NH:60][C:12]([C:9]3[NH:10][C:11]4[C:6]([C:7](=[O:15])[CH:8]=3)=[CH:5][C:4]([O:16][CH3:17])=[CH:3][C:2]=4[Br:1])=[O:14])=[CH:61][CH:62]=2)[CH2:52][CH2:51][O:50][CH2:55][CH2:54]1
Reactant: COc1cc(Br)c2[nH]c(C(=O)O)cc(=O)c2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a yellow suspension of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27a) (3.446 g, 11.56 mmol), TBTU (9.039 g, 28.15 mmol), and HOBt (3.757 g, 27.8 mmol) in 100 mL dimethylformamide was added 4-morpholinoaniline (2.733 g, 15.3 mmol) and diisopropylethyl amine (8.2 mL, 50.2 mmol). The resulting marroon solution was stirred at room temperature under nitrogen for 16 hours during which time the reaction became greenish brown and formed a large amount of precipitate. The reaction mixture was filtered and the solids washed with dimethylformamide, water, and methanol. Drying under high vacuum afforded the desired product as a yellow solid (3.09 g, 58%). 1H NMR (300 MHz, DMSO, d6) δ 12.13 (s, 1 H, NH), 10.18 (s, 1 H, C(O)NH), 7.90 (d, 1 H, Jm=2.7 Hz, ArH5), 7.68 (d, 2 H, Jo=9.0 Hz, ArH2′& H6′), 7.63 (s, 1 H, C═CH), 7.51 (d, 1 H, Jm=2.7 Hz, ArH7), 7.00 (d, 2 H, Jo=9.0 Hz, ArH3′& H5′), 3.94 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N); Mass Spec.: calc. for [C21H20BrN3O4+H]+ Theor. m/z=458, 460; Obs.=458, 460.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]#[N:13])[CH:4]=[CH:3]1.[OH-:14].[K+].O>C(O)(C)(C)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:13])=[O:14])[CH:4]=[CH:3]1
Reactant: [OH-]
Reactant: Cn1ccc2cccc(CC#N)c21
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cn1ccc2cccc(CC(N)=O)c21
Yield: 65.5 %

Procedure:
A slurry of (1-methyl-1H-indol-7-yl)-acetonitrile (137 mmol, crude material prepared as described above) in tert-butanol (240 mL) was heated to reflux, KOH (85%, 88.3 g, 1.57 mol) was added and mixture was stirred at reflux for 15 minutes. H2O (1 mL) was introduced and the mixture was heated at reflux for an additional 5 minutes. The solution was allowed to cool, decanted, and diluted with EtOAc (1 L) and H2O. The two layers were separated and the organic solution was washed with H2O and brine. The crude solution was dried (MgSO4), filtered and concentrated to an off-white solid. Trituration with refluxing ether gave the title compound (16.90 g, 65% from 1H-indole-7-carboxaldehyde). 1H NMR (400 MHz, DMSO-d6) 3.87 (s, 2H), 4.03 (s, 3H), 6.39 (d, J=3.2 Hz, 1H), 6.83–7.01 (m, 3H), 7.20 (d, J=3.3 Hz, 1H), 7.30–7.46 (m, 2H). MS (electrospray, m/z) 189.0 (M++1). Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.03; H, 6.41; N, 14.63.