Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:7][CH2:6][S:5]2=[O:14].[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:7][CH2:6][S:5]2(=[O:15])=[O:14]
Reactant: NS(=O)(=O)c1c(Cl)nc2n1CCS2=O
Reactant: OO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1c(Cl)nc2n1CCS2(=O)=O
Temperature: 100 °C

Procedure:
To a suspension of 0.80 g of 6-chloro-2,3-dihydroimidazo[2,1-b]thiazole-5-sulfonamide-1-oxide in 10 ml of acetic acid is added 4 ml of 30% aqueous hydrogen peroxide solution followed by stirring for hour 100° C. After cooling, ice water is added to the reaction mixture to precipitate crystals. The crystals are collected by filtration, washed with water and dried to give 0.30 g of the title compound as colorless crystals. mp. 246°-247° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:12]([NH:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[NH:19][CH:18]=2)=[O:13])[CH2:11][CH2:10]1.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:18]1[NH:19][C:20]2[C:25](=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:17]=1[CH2:16][CH2:15][NH:14][C:12]([CH:9]1[CH2:11][CH2:10]1)=[O:13]
Reactant: COc1ccc2[nH]cc(CCNC(=O)C3CC3)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(Br)c(CCNC(=O)C3CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
N-bromo succinimide (0.89 g, 5 mmol) was added to a solution of N-cyclopropanoyl-5-methoxytryptamine, 4j (1.29 g, 5 mmol) in acetic acid (20 mL). The reaction mixture was stirred under N2 at room temperature for 4 h, then cooled at 0° C., neutralized with a 50% solution of NaOH and extracted with ethyl acetate. The combined organic layers were washed with NaCl solution, dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel; ethyl acetate/cyclohexane 6:4) and crystallization gave 0.490 g (29% yield) of 4h as white solid, mp 82°-83° C. IR νmax : 3460, 3300, 1650. 1H NMR: 0.72(m, 2H, CH2cyclopropyl), 0.99(m, 2H, CH2cyclopropyl), 1.27(m, 1H, cyclopropyl-CH), 2.93(t, 2H, β -CH2), 3.56(q, 2H, α-CH2), 3.85(s, 3H, OCH3), 5.72(br s, 1H, NH), 6.80-7.25(m, 3Harom), 8.21(br s, 1H, NHindole).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:7]=[N:8][C:9](=[O:12])[NH:10][CH:11]=1>CS(C)=O>[CH3:1][NH:2][C:3]([N:10]1[CH:11]=[C:6]([F:5])[CH:7]=[N:8][C:9]1=[O:12])=[O:4]
Reactant: CN=C=O
Reactant: O=c1ncc(F)c[nH]1
Solvent: CS(C)=O
Product: CNC(=O)n1cc(F)cnc1=O
Yield: 60 %

Procedure:
Methylisocyanate (3.8 mmol) was added dropwise with vigorous stirring to a solution of 5-fluoropyrimidin-2-one (described in Undheim K. and Gacek M. Acta. Chem. Scand 23 (1969) 294) (2.5 mmol) in anhydrous DMSO (3.2 ml). The exothermic reaction started at once and a white solid was precipitated. The precipitate was collected after 50 minutes, washed with a little water, sucked dry, washed with ethyl acetate and dried; yield 60%, m.p. 166° C., 1H NMR (CDCl3): δ3.03 (N-Me), 8.66 (H-4), 8.71 (H-6).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C.C(=O)(O)[O-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Yield: 79.7 %

Procedure:
In a manner similar as described above in Paragraph A, a solution of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine (150 mg, 0.506 mmol) and methyl 4-bromobutanoate (0.29 mL, 2.0 mmol) in THF (6 mL) was treated with triethylamine (0.28 mL, 2 mmol) and the reaction was heated at reflux for 4 hours. The reaction was allowed to cool and treated with an aqueous bicarbonate solution. The combined ethyl acetate extracts were washed with water, dried and concentrated to give 0.16 g of methyl hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-butanoate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:42](O)=[O:43])[CH2:32][C:33]3[CH:38]=[C:37]([Br:39])[C:36]([OH:40])=[C:35]([Br:41])[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:34]=[C:35]([Br:41])[C:36]([OH:40])=[C:37]([Br:39])[CH:38]=3)[C:42]([N:11]3[CH2:12][CH2:13][CH:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)=[O:43])=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CN1CCN(C2CCNCC2)CC1
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: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere 55 mg (0.30 mmol) 1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 151 mg (0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 104 mg (0.27 mmol) HATU and 47 μL (0.27 mmol) ethyldiisopropylamine in 5 mL DMF and the reaction mixture was stirred for 3 h at RT. The reaction solution was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 80:20:2).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][O:1][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl hydroxyacetate (0.80 g, 8.8 mmol) was dissolved in THF (10 mL) and allowed to stir at 0° C. under a nitrogen atmosphere. NaH (0.40 g, 9.6 mmol, 60% dispersion in oil) was added portionwise over approximately 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. 1-Bromo-3-(bromomethyl)benzene (2.0 g, 8.0 mmol) was added in a single portion and the resulting mixture was heated to 40° C. After 4 hours, the reaction mixture was allowed to cool to ambient temperature and partitioned between water and EtOAc. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound, which was carried forward without further purification. 1H NMR (600 MHz, CDCl3): δ 7.53-7.50 (m, 1H), 7.42-7.38 (m, 1H), 7.30-7.17 (m, 2H), 4.57 (s, 2H), 4.09 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.N[C@@H:32]([C:36]1C=CC=C[CH:37]=1)[CH2:33][C:34]#N>>[C:12]([CH2:11][C@@H:10]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:9]1[CH:37]=[CH:36][CH:32]=[CH:33][CH:34]=1)#[N:8]
Reactant: N#CC[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: N#CC[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (3R)-3-amino-3-phenylpropanenitrile (Organic Synthesis 2008, 85, 219-230) instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 388 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.24 (1H, s) 8.79 (1H, d, J=8.44 Hz) 8.02 (1H, d, J=5.42 Hz) 7.85 (1H, d, J=5.47 Hz) 7.51 (1H, d, J=5.47 Hz) 7.44 (2H, d, J=7.18 Hz) 7.22-7.39 (4H, m) 6.84 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.47, 1.22 Hz) 5.46 (1H, td, J=8.63, 6.47 Hz) 3.01-3.22 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].[CH3:22][C:23]1[C:27]([C:28](O)=O)=[C:26]([C:31]([F:34])([F:33])[F:32])[O:25][N:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:28]([C:27]2[C:23]([CH3:22])=[N:24][O:25][C:26]=2[C:31]([F:34])([F:32])[F:33])[O:16][N:15]=1
Reactant: Cc1noc(C(F)(F)F)c1C(=O)O
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C)noc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 3-methyl-5-(trifluoromethyl)-4-isoxazolecarboxylic acid (0.0195 g, 0.1 mmol) and DIEA (0.016 mg, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3-d) δ 7.89 (s, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.46 (d, J=8.4 Hz, 1 H), 5.47 (s, 2 H), 2.97 (t, 2 H), 2.55 (s, 3 H), 1.79-1.70 (m, 2 H), 1.05 (t, 3 H); MS (ES) m/z 450 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[CH:37]=[C:38]2[N:44]=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1>>[N:44]1[C:38]2[C:39](=[N:40][CH:41]=[C:36]([C:18]3[CH:17]=[C:16]4[C:21]([CH2:22][CH:23]([CH3:24])[N:14]([C:12]5[CH:13]=[C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[N:9]=[C:10]([NH2:34])[N:11]=5)[CH2:15]4)=[CH:20][CH:19]=3)[CH:37]=2)[NH:42][CH:43]=1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: Brc1cnc2[nH]cnc2c1
Product: CC1Cc2ccc(-c3cnc4[nH]cnc4c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 116 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (Example 116, Step 1) and 6-bromo-3H-imidazo[4,5-b]pyridine (Focus synthesis, Cat. No. FS000626). LCMS (M+H)+: m/z=456.2.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH:15]([C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:16]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1[nH]c2ccccc2c1C(=O)OC
Yield: 156.9 %

Procedure:
Methyl 2-bromo-1H-indole-3-carboxylate (100 mg, 0.19 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (154 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and cesiumcarbonate (326 mg, 1 mmol) in dioxane/water (20 mL, 5 mL) were stirred at room temperature for 15 hours. Filterated the solid and the solvent was concentrated in vacuum. The resulted residue was purified by silica gel column (ethyl acetate/petroleum ether=1/2) to give methyl 2-vinyl-1H-indole-3-carboxylate as a pale yellow solid (60 mg, 76%) LRMS (M+H+) m/z: calcd 201.1 found 201.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:18](OC)=[O:19])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:5]=[C:4]([CH:18]=[O:19])[CH:3]=1
Reactant: COC(=O)c1cc(Br)n(S(=O)(=O)c2ccc(OC)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution (30 mL) of methyl 5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrole-3-carboxylate (3.00 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (11.0 mL) of diisobutylaluminum hydride in toluene was added dropwise over 15 min, and the mixture was further stirred at −78° C. for 1 hr. A 1.5 mol/l solution (5.0 mL) of diisobutylaluminum hydride in toluene was added, and the mixture was stirred at −78° C. for 15 min, and at 25° C. for 2 hr. 1 mol/l Hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was stirred at 25° C. for 15 min and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (30 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (281 mg), N-methylmorpholine N-oxide (1.41 g) and molecular sieves 4A powder (1.5 g) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown oil (yield 2.07 g, 75%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH3:16])[C:6]=2[CH:5]=1)[CH3:2].F[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH3:16])[C:6]=2[CH:5]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1)[CH3:2]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCNc1ccc2c(c1)C(C)=CCC2(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(c1ccc2c(c1)C(C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 12 %

Procedure:
To a mixture of 1.78 g (8.3 mmol) of ethyl-(5,5,8-trimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 166) and 0.55 g (3.9 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (158 mg).
Reaction SMILES: Br[C:2]1[N:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:17])[C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:7]([C:4]1[N:3]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:17])[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: Cc1cc(C#N)ccc1-n1c(Br)ccc1C=O
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C=O)n2-c2ccc(C#N)cc2C)cc1
Temperature: 90 °C
Yield: 57.1 %

Procedure:
A mixture of compound 50C (24 mg, 0.083 mmol), compound 4-methoxyphenylboronic acid (15.2 mg, 0.1 mmol) and sodium carbonate (17.6 mg, 0.166 mmol) in a mixture of DME (5 mL) and water (1 mL) was degassed, and [11′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (96 mg, 0.008 mmol) was added. The reaction mixture was heated at 90° C. for 10 hours, poured into water, and extracted with ethyl acetate (10 mL×3). The combine organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrate under reduced pressure, and purified by preparative TLC to afford the compound 50D (15 mg, 57%).
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[C:22]([N:24]2[C@H:33]([CH2:34][OH:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].I[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH3:14])=[C:12]([Cl:13])[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH3:39])=[N:9]2)=[C:16]([C:22]([N:24]2[C@H:33]([CH2:34][OH:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:17]=1)[CH3:46]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)OCC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 7.6 %

Procedure:
A mixture of 4-chloro-1-[4-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (intermediate D, 170 mg, 0.31 mmol), ethyl 2-iodoacetate (99 mg, 0.46 mmol), potassium carbonate (13 mg, 0.092 mmol), and triethylamime (0.085 mL, 0.62 mmol) was stirred in acetonitrile (3 mL) at ambient temperature for 12 hours. The solvent was removed in vacuo. The crude material was purified by eluting through a silica gel column with a 10 to 100% ethyl acetate/heptane gradient to afford the title compound (15 mg, 7.6% yield). MS (ESI) [m/e, (M+H)+]=639.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.73-7.39 (m, 7H), 2.51-5.41 (m, 17H), 2.16-2.41 (m, 3H), 0.68-1.70 (m, 16H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=O)[CH:9]=[C:10]([CH:13]=1)[CH:11]=O)[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:9]=[C:10]([CH2:11][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:13]=1)[CH3:2]
Reactant: CC(C)CNCCCNCCCN
Reactant: CCC(CC)COc1cc(C=O)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CC)COc1cc(CNCCCNCCCNCC(C)C)cc(CNCCCNCCCNCC(C)C)c1
Reaction time: 24 h

Procedure:
5-(2-Ethylbutoxyl)isophthalaldehyde (0.20 g, 0.88 mmol) and MeOH (15 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-isobutylpropane-1,3-diamine (0.33 g, 1.76 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.13 g, 3.52 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product a clear oil.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([Cl:20])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1)([OH:9])=[O:8].[OH-].[Na+]>O>[Cl:20][C:13]1[CH:12]=[CH:11][C:10]([C:7]([OH:9])=[O:8])=[CH:15][C:14]=1[S:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(Cl)c(S(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
157.55 g of sodium sulfite (1.25 mol) were dissolved in 725 ml of water and heated to 70° C. At this temperature, 255.08 g of 5-carboxy-2-chlorobenzenesulfonyl chloride were added in portions, the pH (electrode) being kept between 8 and 10 by continuous addition of 320 ml of half-concentrated sodium hydroxide solution (the reaction is slightly exothermic). After the end of the addition, the mixture was subsequently stirred at 70° C. for 2 hours. As soon as the reaction had ended, 5 g of active carbon were added, and after 30 minutes the mixture was filtered hot through a clarifying layer and diluted with 600 ml of water. The solution was allowed to cool to 15°-20° C. and was adjusted to pH 0 using 250 ml of conc. hydrochloric acid, the viscous suspension was stirred in an ice bath for a further 30 minutes and the mixture was then stood well closed in a refrigerator over the weekend. The precipitate was filtered off with suction, washed once with 100 ml of 2N hydrochloric acid and then sucked dry in a stream of air. The substance was sucked dry in vacuo at 50° C.
Reaction SMILES: [C:1]12([C:11](=[O:28])[CH:12](Cl)[C:13]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[O:25][CH3:26])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:29][C:30]1([CH3:37])[O:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]12([C:11](=[O:28])[CH:12]([N:32]3[C:31](=[O:36])[C:30]([CH3:37])([CH3:29])[O:34][C:33]3=[O:35])[C:13]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[O:25][CH3:26])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC1(C)OC(=O)NC1=O
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)C(Cl)C(=O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)C(C(=O)C12CC3CC(CC(C3)C1)C2)N1C(=O)OC(C)(C)C1=O
Yield: 79.7 %

Procedure:
A suspension of 16.28 g (0.04 mol) of [4], 5.17 g (0.04 mol) of 5,5-dimethyloxazolidine-2,4-dione, and 16.58 g (0.12) mol of anhydrous potassium carbonate in 380 mL of dried acetone was refluxed for 3 hours. Thin layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was concentrated in vacuo to yield an orange-colored solid. It was dissolved in ethyl acetate and the organic layer was washed with HCl (10%) and brine until neutrality. The organic layer was dried, filtered, and concentrated to yield an oil which solidified upon standing. It was triturated in ligroin. The final dried product (15.92 g, 79.8%) gave one spot on TLC. All analytical data confirmed the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Cc1cccc(I)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccc(C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-iodotoluene.