Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])/[C:4](/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1)=[CH:5]/[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:14]=2)/[C:3]([OH:27])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Yield: 71.5 %

Procedure:
A solution of (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (387 mg, 0.96 mmol) in ethanol (6 mL) was treated with a 1N aqueous sodium hydroxide solution (2 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×35 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the (E)-3-cycloheptyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (268 mg, 72%) as a brown solid: mp 151-156° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C@H:15]1[O:19][C:18](=[O:20])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:16]1)([CH3:14])([CH3:13])[CH3:12].[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[C:11]([C@H:15]1[O:19][C:18](=[O:20])[C@@:17]([C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:16]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[C@H]1OC(=O)C(c2ccccc2)O1
Reactant: O=C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCCC2)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 1 M lithium bis(trimethylsilyl)amide in hexanes (1 litre, 1 mol) is added dropwise (R)-2-tert-butyl-5-phenyl-[1,3]dioxolan-4-one (170 g, 0.77 mol) in THF (1.1 litre) over 90 minutes ensuring the temperature does not exceed −70° C. After stirring at −78° C. for 1 hour, cyclohexanone (112 ml, 1.1 mol) is added dropwise over 15 minutes and then stirring continued at −78° C. for another hour. The reaction is quenched by addition of 10% aqueous ammonium chloride solution (170 ml) and after warming to −20° C., a further 2 litres of 10% aqueous ammonium chloride solution is added. The aqueous portion is separated and extracted with EtOAc (500 ml). The organic portions are combined, dried over MgSO4 and concentrated in vacuo. The resulting crude product is slurried in heptane for 20 minutes and then filtered and dried in vacuo to afford the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1
Reactant: COc1ccccc1-c1csc(N)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1-c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Methoxy-phenyl)-thiazol-2-ylamine (41.3 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (11.4 mg, 0.0367 mmol, 18.4%). ESI-MS m/z calc. 310.1. found 311.2 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: Cl.[CH:2]([O:5][NH2:6])([CH3:4])[CH3:3].Cl.CON.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:22][C:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:23]1[N:6]([O:5][CH:2]([CH3:4])[CH3:3])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CC(C)ON
Agent: CON
Agent: Cl
Product: CCCCc1nc2cnc3ccccc3c2n1OC(C)C
Yield: 72.7 %

Procedure:
The method of Part B of Example 25 was followed using O-isopropylhydroxylamine hydrochloride (2.4 g, 21 mmol) in lieu of O-methylhydroxylamine hydrochloride to treat N-(4-chloroquinolin-3-yl)pentanamide (4.5 g, 17 mmol) with the modification that the reaction was heated at reflux overnight. 2-Butyl-1-isopropoxy-1H-imidazo[4,5-c]quinoline (3.5 g) was obtained as a dark oil.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)[CH3:3].[C:23]1([NH:29][C:30](=[O:43])[C:31](=[N:35]NC2C=CC=CC=2)[C:32](=O)[CH3:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Zn].C(O)(=O)C>[CH2:2]([N:4]1[CH2:13][CH2:12][C@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@H:6]([CH2:7][C:8]3[C:32]([CH3:33])=[C:31]([C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:43])[NH:35][C:9]=3[CH2:10]2)[CH2:5]1)[CH3:3]
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)Nc1ccccc1
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)Nc4ccccc4)c(C)c3C[C@@H]2C1
Yield: 25.6 %

Procedure:
0.8 g (2.47 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.7 g (2.47 mmol) of N-phenyl-2-phenylhydrazono-3-oxobutyramide, 0.24 g (3 mmol) of CH3 COONa, 0.74 g (11.3 mmol) of zinc dust and 2.5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by flash chromatography (EtOAc/MeOH/conc. NH4OH 90:10:1) yielding 0.28 g of the title compound. M.p.=178-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)(OC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:12]([C:13]3[O:14][C:23]([CH3:24])=[N:16][N:15]=3)=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)Nc1cc(Nc2ccc(F)cc2)ncc1C(=O)NN
Agent: COC(C)(OC)OC
Product: Cc1nnc(-c2cnc(Nc3ccc(F)cc3)cc2NC(C)C)o1

Procedure:
A solution of 6-((4-fluorophenyl)amino)-4-(isopropylamino)nicotinohydrazide (91) (100 mg) and PTSA (10 mg) in trimethyl orthoacetate (5 mL) was heated at 100° C., overnight. The reaction mixture was concentrated, diluted with EtOAc. The organic layer was washed with sat. NaHCO3 solution, water and brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by prep. HPLC to afford N2-(4-fluorophenyl)-N4-isopropyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 149).
Reaction SMILES: O=S1(=O)CCC(NCCN[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC2)C1.[CH3:50][C@:51]12[C@@:68]3([CH3:69])[C@@H:59]([C@:60]4([CH3:81])[C@@H:65]([CH2:66][CH2:67]3)[C:64]([CH3:71])([CH3:70])[C:63]([C:72]3[CH:80]=[CH:79][C:75]([C:76]([OH:78])=[O:77])=[CH:74][CH:73]=3)=[CH:62][CH2:61]4)[CH2:58][CH2:57][C@@H:56]1[C@H:55]1[C@H:82]([C:85]([CH3:87])=[CH2:86])[CH2:83][CH2:84][C@:54]1([NH:88][CH2:89][CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1)[CH2:53][CH2:52]2>>[CH:85]([C@H:82]1[C@@H:55]2[C@@H:56]3[C@@:51]([CH3:50])([CH2:52][CH2:53][C@@:54]2([NH:88][CH2:89][CH2:90][CH2:91][N:92]2[CH2:93][CH2:94][O:95][CH2:96][CH2:97]2)[CH2:84][CH2:83]1)[C@@:68]1([CH3:69])[C@@H:59]([C@:60]2([CH3:81])[C@@H:65]([CH2:66][CH2:67]1)[C:64]([CH3:70])([CH3:71])[C:63]([C:72]1[CH:73]=[CH:74][C:75]([C:76]([OH:78])=[O:77])=[CH:79][CH:80]=1)=[CH:62][CH2:61]2)[CH2:58][CH2:57]3)([CH3:87])[CH3:86]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CC(C)[C@@H]1CC[C@]2(NCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((3-morpholinopropyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as the starting material. The product was isolated as a white solid (5 mg, 40%). LCMS: m/e 659.55 (M+H)+, 2.86 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.38 (d, J=4.6 Hz, 1H), 3.98 (br. s., 4H), 3.47-3.14 (m, 6H), 2.58-2.34 (m, 1H), 2.30-1.04 (m, 27H), 1.21 (s, 3H), 1.11 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H), 0.93 (d, J=6.7 Hz, 4H), 0.86 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:37]=[CH:36][C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][C:22](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:24]=4)[CH2:19]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:38]([O:40]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:39].[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.Cl.O>[C:38]([C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:37][CH:36]=3)[CH2:19]2)=[CH:24][CH:23]=1)(=[O:40])[CH3:39]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
2-(4-(4-Phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (0.515 g, 0.97 mmol), (1-ethoxyvinyl)tributyltin (0.420 g, 1.16 mmol), lithium chloride (0.121 g, 2.85 mmol) and tetrakis-(triphenylphosphine)palladium (0) (0.057 g, 0.05 mmol) in 1,4-dioxane (15 ml) were heated at reflux under argon for 16 h. The cooled reaction mixture was treated with water (2.0 ml) and aqueous 5N hydrogen chloride (4 drops), then stirred at room temperature for 0.5 h. The resulting solution was poured onto saturated, aqueous potassium carbonate (20 ml) and the product was extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (40 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 50-100% ethyl acetate--pentane gradient elution to afford the title compound as a colourless solid (0.210 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH2:18][OH:19].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH:18]=[O:19]
Reactant: O=c1[nH]c2ccc(Br)cc2c(CO)c1-c1cccs1
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c(-c2cccs2)c(=O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-4-(hydroxymethyl)-3-(thiophen-2-yl)quinolin-2(1H)-one (0.155 g, 0.461 mmol) in acetonitrile (4.60 ml) were added bisacetoxy iodobenzene (0.134 g, 0.415 mmol) and 2,2,6,6-tetramethyl piperidin-1-oxyl (7.30 mg, 0.046 mmol). The reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with ethyl acetate (30 ml) and extracted with saturated sodium thiosulfate (1×25 ml), sodium bicarbonate (1×25 ml) and sodium chloride (1×25 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification of the crude oil by silica chromatography gave 6-bromo-2-oxo-3-(thiophen-2-yl)-1,2-dihydroquinoline-4-carbaldehyde as a white solid. LCMS (M+H)=335.76.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][P:20]([CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)([O:21][CH2:22][CH3:23])=[O:24])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cnc(NC(=O)OC(C)(C)C)cn1)OCC
Temperature: 140 °C
Yield: 59.8 %

Procedure:
tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (2.5 g, 8.71 mmol) and triethylphosphite (1.8 ml, 10.45 mmol) were placed in a 25 mL round bottom flask. A distillation apparatus was attached to collect the poisonous ethyl bromide formed during the reaction. The reaction mixture was heated to 140° C. for 30 minutes and then cooled to room temperature. The reaction mixture was purified by flash column chromatography (10% to 30% Ethyl acetate/Hexane) to afford title product (1.8 g, 60% yield). 1H NMR (600 MHz, CDCl3) δ 9.19 (s, 1H), 8.22 (t, J=1.8 Hz, 1H), 7.37 (s, 1H), 4.12-4.07 (m, 4H), 3.38 (s, 1H), 3.34 (s, 1H), 1.54 (s, 9H), 1.29 (t, J=7.2 Hz, 6H). MS m/z: 346 [M+1].
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:5]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 70 %

Procedure:
Condensation of BocProOSu (6.00 g.) and HDTrpOH (4.08 g.) by the salt coupling method gave BocPro-DTrpOH in 70% yield. Condensation of BocPro-DTrpOH (2.93 g.) and HGlyOBz p-toluenesulfonate salt (2.47 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-GlyOBz in 68% yield. Debenzylation of BocPro-DTrp-GlyOBz by hydrogenation with palladium catalyst gave BocPro-DTrp-GlyOH in 95% yield.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][N:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([F:19])=[C:14]([CH:18]=3)[C:15]([OH:17])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:32]([N:35]1[CH:39]=[N:38][N:37]=[C:36]1[C:40]1[N:45]=[C:44]([NH2:46])[CH:43]=[CH:42][CH:41]=1)([CH3:34])[CH3:33].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][N:8]([C:10]3[C:11]([CH3:20])=[CH:12][C:13]([F:19])=[C:14]([CH:18]=3)[C:15]([NH:46][C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([C:36]4[N:35]([CH:32]([CH3:34])[CH3:33])[CH:39]=[N:38][N:37]=4)[N:45]=3)=[O:17])[CH:9]=2)[CH2:3][CH2:4]1
Reactant: CC(C)n1cnnc1-c1cccc(N)n1
Reactant: Cc1cc(F)c(C(=O)O)cc1-n1cnc(C2CC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cc(F)c(C(=O)Nc2cccc(-c3nncn3C(C)C)n2)cc1-n1cnc(C2CC2)c1

Procedure:
5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (1.5 g, 5.07 mmol) was suspended in anhydrous 1,2-dichloromethane (25 mL) at room temperature. Oxalyl chloride (0.575 ml, 6.59 mmol) was added with stirring under nitrogen, followed by N,N-dimethylformamide (0.044 ml, 0.507 mmol). The mixture was stirred for 4 hr at room temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in 25 mL anhydrous dichloromethane. 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (1.13 g, 5.58 mmol) (compound C) and 4-dimethylaminopyridine (0.62 g, 5.07 mmol) were rapidly added with stirring under nitrogen. The reaction was stirred for 2 hours at room temperature and aqueous saturated NaHCO3 (15 mL) was added. The mixture was stirred for 10 minutes, and the layers were separated, and the aqueous layer was washed 1×20 mL dichloromethane. The combined organics were dried (MgSO4), filtered and concentrated. The residue was dissolved in a minimum amount of CH3CN and water was slowly added until solids precipitated from the mixture. The solid was collected by filtration and dried to give 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide in ˜96% purity (1.28 g, 2.88 mmol). Anal. LC/MS (m/z: 446, M+1). The material was further purified by RP-HPLC (reverse phase HPLC) to obtain an analytically pure sample as the HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH2:33]([O:32][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[C:22]([CH2:21][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])[CH:23]=[N:24]2)=[CH:29][CH:28]=1)[CH3:34]
Reactant: CCOc1ccc2cc(CCl)cnc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc2cc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cnc2c1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (112 mg, 511 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.48 mL, 0.96 mmol) at RT followed by CCH 29190 (110 mg, 426 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 47 mg of 4-((7-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. The free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.09 M HCl in MeOH (4 mL) and the solution was stirred for 5 min at RT, and concentrated at 40° C. under vacuum to afford 4-((7-ethoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 30 as a yellow solid (56 mg, 28% yield).
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[CH:27]1([B-](F)(F)F)[CH2:29][CH2:28]1.[K+]>>[C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:27]2[CH2:29][CH2:28]2)=[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Oc2ccc(F)cc2)n1)C(N)=O
Reactant: F[B-](F)(F)C1CC1
Agent: [K+]
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(Oc2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 166 b, using 5-bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (Example 177 b) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e=386.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH:18]=1>CN(C=O)C.O.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:17]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(C2=CCCC2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
5-Bromo-pyridine-2-carboxylic acid (CAN 30766-11-1, 3.4 g, 17 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 530 mg, 0.65 mmol) and Cs2CO3 (6.3 g, 19 mmol) were added to a solution of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9, 2.5 g, 13 mmol) in DMF (50 mL) and water (10 mL). The mixture was stirred at 150° C. overnight and concentrated in vacuo. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound (1.0 g, 31%); MS (EI): m/e=190.1 [M+H]+.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I.Cl>C1COCC1>[Cl:13][C:14]1[N:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([I:24])=[CH:18][CH:19]=1
Reactant: II
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: FC(F)(F)c1nc(Cl)ccc1I
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7.1 ml of n-BuLi (1.6M in hexane, 11.3 mmol) in 7 ml THF under argon at −73° C. were added 1.6 ml of diisopropylamine (11.3 mmol) in 3 ml THF within 8 min. After 10 min stirring at the same temperature a solution of 1 g of 2-chloro-6-(trifluoromethyl)-pyridine (5.51 mmol) in 5 ml THF was added within 15 min (temperature between −76 and −75° C.). The dark brown solution was stirred at −75° C. for 1 h 15 min. Finally a solution of 1.4 g of iodine (5.51 mmol) in 10 ml THF was added at −75° C. over 25 min. After additional 45 min stirring at the same temperature 12 ml 2M aqueous HCl were added within 2 min (temperature raised from −78 to −50° C. The cooling device was then removed, the reaction mixture diluted with diethylether. After separation of the organic phase, the aqueous phase was reextracted with diethylether. The combined organic phases were successively washed with 10 ml 1M sodium thiosulfate, saturated NaHCO3 and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo to yield 1.54 (69%) of 6-chloro-3-iodo-2-trifluoromethyl-pyridine as a brown semisolid residue. MS: 307.0