Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH2:18][OH:19].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:17]1[CH2:18][O:19][C:12]2([CH2:13][CH2:14][CH2:15][CH:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:11]2)[O:16]1
Reactant: OCCO
Reactant: O=C1CCCC(S(=O)(=O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)C1CCCC2(C1)OCCO2
Yield: 97 %

Procedure:
To a solution of 5.3 g of 3-(phenylsulfonyl)-cyclohexan-1-one in 60 ml of benzene, were added 0.3 ml of 1,2-ethanediol and 0.2 g of anhydrous paratoluenesulfonic acid. The reaction mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and then, dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl ether, whereby 6.1 g of 1,1-(ethylenedioxy)-3-(phenylsulfonyl)-cyclohexane were obtained in the form of white crystals. Yield: 97%
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:31])[C:17]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[C:19]([CH3:25])[C:18]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>C(O)C>[CH:27]1([O:26][C:18]2[C:19]([CH3:25])=[CH:20][C:21]([CH2:23][OH:24])=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:31])[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cc(CO)cc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CO)cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
2-(2-Cyclobutoxy-5-hydroxymethyl-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (70 mg, 0.16 mmol) is dissolved in ethanol (1.5 mL), and solid KOH (191 mg, 3.3 mmol) and water (1504) are added. The mixture is stirred at room temperature for 30 min then concentrated in vacuo. The residue is dissolved in water (1.5 mL) and acidified with conc. HCl until no more white solid precipitated. The mixture is extracted with ethyl acetate (2×8 mL) and the combined organic layers are concentrated in vacuo to give product (286) as white solid (60 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[CH:7]=1.Br[C:26]1[S:27][C:28]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[C:33]([C@H:42]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:32]([CH3:53])=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[C:49]([O:48][C@@H:42]([C:33]1[C:32]([CH3:53])=[CH:31][C:29]2[N:30]=[C:26]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:6]4[CH:7]=[C:2]([CH3:1])[C:3](=[O:24])[NH:4][C:5]4=[O:23])[CH:9]=3)[S:27][C:28]=2[C:34]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:50])([CH3:51])[CH3:52]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1cn(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)c(=O)[nH]c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-n4cc(C)c(=O)[nH]c4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture 5-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (50 mg, 0.154 mmol), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (51 mg, 0.103 mmol), Pd(PPh3)4 (12 mg, 0.01034 mmol) and 2M potassium carbonate (0.15 mL, 0.309 mmol) was heated at 105-120° C. for 5 h. Reaction mixture was stirred over the weekend at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). Product-containing fractions were diluted with ethyl acetate, washed with saturated sodium bicarbonate solution/brine. Organic layer was dried (MgSO4), filtered, and concentrated to give desired product. LCMS-ESI+: calc'd for C33H33ClN3O5S: 618.2 (M+H+); Found: 618.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]=[C:14](I)[CH:13]=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(C([Sn])=C(CCCC)CCCC)CCC.[F-].[K+]>CC#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH:15]=[C:14]([CH:17]=[CH2:18])[CH:13]=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)n1cc(I)cn1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd]
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: C=Cc1cnn(C(=O)OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-iodopyrazole-1-carboxylic acid benzyl ester (2.03 g, 6.20 mmol), Pd2(dba)3 (120 mg, 0.131 mmol), P(o-tolyl)3 (283 mg, 0.929 mmol) and tributylvinyltin (2.71 mL, 9.28 mmol) in CH3CN (15 ml) is heated at 80° C. for 3 h. The mixture is cooled to RT, stirred with aq. KF for 15 min and filtered through Celite. The filtrate is partitioned between EtOAc and brine. The organic layer is dried over MgSO4, concentrated and chromatographed to afford the title compound as a light yellow solid: 1H NMR (CDCl3) δ 8.06 (s, 1H), 7.84 (s, 1H), 7.50-7.32 (m, 5H), 6.51 (dd, J=16.0, 12.0 Hz, 1H), 5.60 (d, J=16.0 Hz, 1H), 5.46 (s, 2H), 5.26 (d, J=12.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)CCC>>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[C:13]([C:11]([N:9]2[CH2:10][C:5]3[C:6](=[N:7][C:2]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=4)=[CH:3][CH:4]=3)[CH2:8]2)=[O:12])[CH:18]=1)(=[O:21])=[O:20]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C(F)(F)F)c1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3cccc(C(F)(F)F)c3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and tributyl-[3-(trifluoromethyl)phenyl]-stannane. White solid. MS (m/e): 559.2 [M+H]+, 100%).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:27])[CH2:4][O:5][C:6]1[C:14]([Br:15])=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:16][C@@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:8][CH:7]=1.[CH:28]([O:30][CH2:31][CH3:32])=[CH2:29]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:14]1[C:6]([O:5][CH2:4][CH:3]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[CH2:2][Br:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][C@@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH3:18])[N:11]=[CH:10]2
Reactant: C=COCC
Reactant: C[C@@H](Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(C)OC(CBr)COc1ccc2cnn(C[C@H](C)O[Si](C)(C)C(C)(C)C)c2c1Br
Yield: 85.1 %

Procedure:
To a solution of the product from Step E (1.85 g, 3.54 mmol) and p-toluenesulfonic acid (0.01 g) in dichloromethane (50 mL) at 0° C. was added ethyl vinyl ether (1 mL, 10.5 mmol). After 30 min the reaction was quenched with a saturated solution of sodium bicarbonate (50 mL) and extracted with EtOAc (3×80 mL). Evaporation and purification by chromatography (silica, 1% to 8% EtOAc/hexane) gave a viscous oil (1.79 g, 81%): LC/MS (+APCI) m/z 595 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([O:14]CC)=[O:13])[NH:9]2)=[C:4]([CH2:18][CH3:19])[CH:3]=1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[C:4]([CH2:18][CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(CC)cc(Cl)cc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1cc(Cl)cc2[nH]c(C(=O)O)cc(=O)c12
Yield: 98.7 %

Procedure:
Treatment of ethyl 7-chloro-5-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (250 mg) with 2M is NAOH (1.5 ml) in DMF at room temperature for 76 h, followed by acidification with HCl, gave 7-chloro-5-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (222 mg), mp 282°-283° C. δ (360 MHz, DMSO-d6) 1.15 (3H, t, CH3), 3.26 (2H, q, CH2), 6.55 (1H, s, 3-H), 7.10 (1H, d, 6-H), 7.88 (1H, d, 8-H) and 11.78 (1H, bs, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][N:14]1CCCC1=O>Cl.O>[C:13]([C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11])#[N:14]
Reactant: CCCCc1ccc(O)cc1Br
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: O
Product: CCCCc1ccc(O)cc1C#N
Temperature: 25 °C

Procedure:
16.0 g (0.07 mol) of the 3-bromo-4-n-butylphenol prepared in Step IV was dissolved in 70 ml of N-methyl-2-pyrrolidone. 6.5 g (0.073 mol) cuprous cyanide was added to the suspension which was refluxed for four hours. The reaction mixture was cooled to room temperature and poured into a solution of 26 g ferric chloride hexahydrate dissolved in a mixed solution of 10 ml of concentrated hydrochloric acid and 47 ml of water. The resultant solution was stirred with heating for 30 minutes at 65° C. in order to decompose nitrile complexes with cuprous bromide. Next, the suspension was poured into 300 ml of cold water, and an organic layer which separated out was extracted with ether. After the organic layer was clearned with acid, alkali and water and was dehydrated with anhydrous sodium sulfate, ether in the organic layer was distilled off. The residue was distilled under vacuum (115° C./1 mmHg) to yield 8.4 g of purified 3-cyano-4-n-butylphenol. The yield was calculated to be 68.2%.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.064 g, 65%). MP: 71-78° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.50 (s, 1H), 8.55 (d, 1H, J=8.3 Hz), 8.16 (s, 1H), 7.99 (s, 1H), 7.95-7.91 (m, 1H), 7.63-7.57 (m, 1H), 7.50 (s, 1H), 7.29-7.23 (m, 1H), 6.65 (s, 1H), 5.91 (tt, 1H, J=56.1 Hz and 4.2 Hz), 3.87 (s, 3H), 3.26 (sept, 1H, J=6.9 Hz), 2.97-2.70 (m, 10H, 1.32 (d, 6H, J=7.1 Hz). MS: 566.49 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:8]=3.[Cl:24][C:25]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:24][C:25]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=4)[CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(Cl)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(-c3cccnc3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(-c3cccnc3)ccc12
Temperature: 105 °C

Procedure:
To the reaction mixture above (481B) was added 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine 477B (0.098 g, 0.289 mmol) and additional PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.024 mmol). The mixture was heated in microwave at 105° C. for 1 hr. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 495.19 (M−H)−.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35]C)=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16]2([CH2:30]OC(C)(C)O[CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.[CH2:61]([N:63]([CH2:67][CH3:68])[CH2:64][CH2:65][NH2:66])[CH3:62]>CO.C1COCC1.CC#N>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([OH:35])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16]2([CH2:30][N:66]([CH2:65][CH2:64][N:63]([CH2:67][CH3:68])[CH2:61][CH3:62])[CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)COC(C)(C)OC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCN1CC2(COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)O)cc4n3C2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
TsOH monohydrate (1 eq.) was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate (Example 2, Step 3) in MeOH/THF 1:3 (0.03 M), and the solution was stirred at RT for 6 h. Filtration on a pad of neutral alumina using EtOAc as eluent afforded after evaporation of the solvent in vacuo, methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (91%). Triflic anhydride (3.5 eq) was added at 0° C. to a solution of this material in dry MeCN (0.05M), DIPEA (4.0 eq) was added and the mixture was stirred at 0° C. for 15 min, then further 4.0 eq of DIPEA were added; N,N-diethylethane-1,2-diamine (2 eq) was added, and the mixture was stirred at 70° C. for 2 h. After removal of the solvent EtOAc was added, the organic phase was washed with water and brine, dried over Na2SO4 and the solvent was removed in vacuo. The residue was hydrolysed with aq. 1N KOH in dioxane (75° C., 2 h) under degassed conditions; after quenching at 0° C. with 1N HCl evaporation to dryness gave a residue that was purified by RP-HPLC to afford the title compound (TFA salt, 25%). 1H NMR (600 MHz, DMSO-d6, 300 K) 1.15-1.37 (m, 3H), 1.22 (t, 7.1, 6H), 1.57 (bd, J 11.6, 1H), 1.67-1.74 (m, 2H), 1.84 (bd, J 11.6, 1H), 1.90-2.02 (m, 3H), 2.64-2.68 (m, 1H), 3.18 (q, J 7.1, 4H), 3.24-3.30 (m, 2H), 3.74 (bs, 2H), 3.86 (d, J 10.4, 1H), 3.95 (bd, J 15, 1H), 4.09 (d, J 10.8, 1H), 4.14 (d, J 10.4, 1H), 4.24 (bd, J 12.5, 1H), 4.28 (bd, J 12.5, 1H), 4.37 (d, J 10.8, 1H), 5.21 (bd, J 15, 1H), 7.20-7.22 (m, 3H), 7.48-7.51 (m, 1H), 7.69 (d, J 8.4, 1H), 7.90 (d, J 8.4, 1H), 8.55 (s, 1H); MS (ES+) m/z 516 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCN(C)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(C)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 14 %

Procedure:
According to general procedure B, 4-bromo-N-ethyl-N-methylbenzenesulfonamide (111 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-N-methylbenzenesulfonamide (17 mg, 14%) was provided after purification. MS (ESI) m/z 303. HPLC purity 99.5% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: N1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[N:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])N=1.C(O)(=O)[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)N.C(ON=O)CC(C)C>O1CCOCC1.C(OCC)C>[CH2:7]1[C:6]2[C:5](=[N:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:17]3[C:18]=2[CH:20]=[CH:21][CH:22]=[CH:23]3)[CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1nnc2c(n1)CCCC2
Reactant: Nc1ccccc1C(=O)O
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1nc2c(c3ccccc13)CCCC2

Procedure:
Analogously to the method described by Gonsalves et al. (Tetrahedron 1992, 48, 6821) a solution of 3.90 g of ethyl 5,6,7,8-tetrahydro-benzo[1,2,4]triazin-3-carboxylate (Sagi et al., Heterocycles 1989, 29, 2253) in 20 ml dioxane is refluxed. Then 8.22 g of anthranilic acid and 7.02 g of isoamylnitrite, in each case dissolved in 20 ml dioxane, are simultaneously added dropwise within 25 minutes by means of two dropping funnels. The reaction mixture is refluxed for a further 30 minutes. For working up the cooled deep-brown reaction solution is diluted with 150 ml diethyl ether, washed with 100 ml of 2 N sodium hydroxide solution and with water, dried over magnesium sulphate and evaporated down. The brown, oily flask residue is chromatographed through a silica gel column with ethyl acetate/petroleum ether (20:80 to 50:50) as eluant. The product obtained is still somewhat contaminated, but is reacted further without any more purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3cccnc3F)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3cccnc3F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(O[Na])(C)(C)C.C(=[NH:70])(C1C=CC=CC=1)C1C=CC=CC=1.O.NO.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([NH2:70])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(N)cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 4-(5-bromo-3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (4.83 g), palladium(II) acetate (384 mg), (±)-2-(di-tert-butylphosphino)-1,1′-binaphthyl (1.06 g), and tert-butoxysodium (1.97 g) in toluene (34 ml) was added benzophenone imine (2.29 ml), stirred at 120° C. for 3.5 hours, then ethanol (34 ml), water (34 ml), hydroxylamine monohydrate (4.0 g), and sodium acetate (6.73 g) were added thereto at room temperature, and stirred at room temperature for 4 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate) to give 4-(5-amino-3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (2.4 g) as a yellow oil.
Reaction SMILES: B.C1COCC1.[I:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1>[I:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1I
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1I

Procedure:
Borane-THF (1.0M solution in THF; 94 mL; 94 mmol) was added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzoic acid (2.97 g; 9.4 mmol) in THF (300 mL) at 0° C. under N2. The reaction was heated at reflux for 90 min and then carefully quenched with 6N HCl until no further gas evolution. The reaction was diluted with H2O (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid. LCMS=285.0 (M−17)+. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, J=8.3 Hz, 1 H), 7.79 (s, 1 H), 7.28 (d, J=8.4 Hz, 1 H), 4.75 (s, 2 H). An alternative procedure is as follows: To a solution of 2-Iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A, 9 g) in THF (100 mL) and water (10 mL) at 0° C. was added NaBH4 (0.5 g). The reaction was stirred 30 minutes. To the reaction mixture was added dilute aqueous HCl (cautiously). The mixture was extracted with ether and the ether layer was washed with water, then brine. The ether layer was then dried over anhydrous MgSO4, filtered and concentrated. The material is chromatographed on SiO2 using a step gradient of 1:3 CH2Cl2/hexanes, then 1:1 CH2Cl2/hexanes, then 100% CH2Cl2 to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.