Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([O:17]C)[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)Cl.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OC)cccc2cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(O)cccc2cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium iodide (3.74 g, 10.12 mmol, 1.3 equiv) was added to a solution of 3-chloro-8-methoxy-naphthalene-2-carboxylic acid ethyl ester (2.06 g, 7.79 mmol) in anhydrous CH2Cl2 (39 ml). After cooling to −78° C., BCl3 (1M solution in CH2Cl2, 19.46 ml, 19.46 mmol, 2.5 equiv) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then let warm to room temperature. After 2 hours at room temperature, cold water (4° C., 40 ml) was added slowly, and the resulting mixture was vigorously stirred for 30 minutes before it was extracted with EtOAc (800 ml total). The combined organic layers were washed with concentrated aqueous NaHCO3 solution (100 ml) and concentrated aqueous NH4Cl solution (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of hexane/EtOAc 100:0 to 6:4) afforded the title compound (1.84 g, 95%, inseparable 1:1.3 mixture of regioisomers A:B) as a slightly yellow solid. 1H NMR (400 MHz, d6-DMSO): δ=10.69 (br s, 1H isomer B), 10.55 (br s, 1H isomer A), 8.60 (s, 1H isomer B), 8.35 (s, 1H isomer A), 8.16 (s, 1H isomer A), 8.06 (s, 1H isomer B), 7.55-7.36 (m, 2H isomer A+2H isomer B), 7.01 (d, J=7.6 Hz, 1H isomer A), 6.95 (d, J=7.5 Hz, 1H isomer B), 4.36 (q, J=7.1 Hz, 2H isomer A+2H isomer B), 1.37-1.33 (m, 3H isomer A+3H isomer B). MS (ES+): 251 (M+H)+.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([NH:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:25]1([CH2:28][N:20]([CH2:21][CH2:22][CH3:23])[C:16]2[C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:2]4[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=4[CH3:24])=[N:11][C:12]=3[CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]1
Reactant: CCCNc1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CC1CC1)c1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To 0.041 g (0.13 mmol) of N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine in 2 mL of methanol was added 95 μL (1.3 mmol) of cyclopropane carboxaldehyde, 200 μL of glacial acetic acid and 0.032 g (0.51 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude solid was partitioned between saturated sodium bicarbonate and dichloromethane, the organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified by reverse-phase HPLC to give 0.026 g (42%) of the title compound as a colorless sticky solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:11][O:12][C:13](=[O:33])NCCCCCCCCCCCCCCCCCC)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(SCC(OC)C[NH2:54])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12.CNC(OC(COC(=O)N[CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])CN)=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:11][O:12][C:13]([CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:33])[CH2:10][NH2:54])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(C)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCC(=O)OCC(CN)NC(=O)OC(C)(C)C

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropane V e2 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 127°-129° C., The amino compound IV e2 69°-70° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Sn](=O)CCCC)CCC.[N:51]([Si](C)(C)C)=[N+:52]=[N-:53].C1(C)C=CC=CC=1>C(OCC)(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:53][N:52]=[N:51][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 23.1 %

Procedure:
A mixture of 4′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.08 g), dibutyltin oxide (0.0037 g), azidotrimethylsilane (0.26 g) and toluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.02 g, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Br:11])[CH:4]=1)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N)c(Br)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over 0.5 hours at below 40° C. After 15 minutes, the mixture is washed with H2O (4×100 ml). The solution is dried (MgSO4) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59°-62° C. A 35 g sample of this material in 180 ml of dry dimethylformamide is stirred and heated at reflux with 17.57 g of Cu2 (CN)2 for 6 hours under N2 atmosphere. Subsequently, 180 ml of FeCl3 /HCl solution (40 g FeCl3.6H2O/10 ml concentrated HCl/60 ml H2) is added and the mixture is heated for 2 minutes at 60°-70° C. and poured into 350 ml of H2O. The aqueous mixture is extracted with CH2Cl2 and the extracts are washed with H2O, saturated NaHCO3 solution and H2O, respectively. The CH2Cl2 solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to afford 14.25 g, mp 155°-159° C., of 4-amino-3-cyanoacetophenone. A 4.8 g sample of this product in 100 ml of EtOAc and 100 ml of CHCl3 containing 13.32 g of CuBr2 is heated at reflux temperature for 20 minutes. The mixture is further heated after 20 ml of EtOh is added and then filtered while still hot. The filter cake is washed with 50 ml of hot 20% MeOH/CH2Cl2 and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 ml of CH2Cl2 and the solid is collected and washed with CH2Cl2 to give 8.08 g of the phenacyl bromide. This material is added to 50 ml of t-BuNH2 in 100 ml of EtOH at 5° under N2 atmosphere. After 10 minutes of stirring, the mixture is allowed to warm to 30° C. to give a solution. This solution is cooled to 10° and 4 g of NaBH4 is added in portions. After 45 minutes, the mixture is allowed to warm (42° C.) and kept at 20° C. until the exotherm subsides. The mixture is then evaporated to dryness and the residue is washed with H2O. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution is filtered. The filter cake is further washed with hot MeOH and the combined filtrates are concentrated to afford crystals. This solid is recrystallized from MeOH/2-PrOH to afford 2.08 g, mp 184°-186° C., of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=CC=1[C:62]([F:65])([F:64])[F:63])#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:62]([F:65])([F:64])[F:63])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2-(trifluoromethyl)benzene in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1>O1CCOCC1.O.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]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)[CH:20]=[N:19][C:5]=3[NH:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1c2cc(Br)cnc2NCN1Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)C(=O)N(Cc3ccc(F)cc3)CN4)cc12
Temperature: 100 °C
Yield: 42.2 %

Procedure:
To a solution of 6-bromo-3-(4-fluorobenzyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (110 mg, 0.33 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.30 mmol) and K3PO4.3H2O (159 mg, 0.60 mmol) in dioxane/water (2 mL/0.2 mL) was added Pd(dppf)Cl2 (10 mg) under nitrogen. The mixture was heated at 100° C. for 5 h, and after being concentrated in vacuo, the residue was suspended in water. The suspension was extracted with EtOAc and the organic phase was washed with brine and dried over sodium sulfate. Finally, 5-(3-(4-fluorobenzyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, yield: 42%) was obtained by the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.27˜9.00 (m, 2H), 7.93˜7.96 (m, 2H), 7.80 (s, 1H), 7.64 (s, 1H), 7.33˜7.36 (m, 2H), 7.20 (t, J=8.8 Hz, 2H), 7.05 (t, J=8.4 Hz, 2H), 5.85 (br s, 1H), 5.26 (br s, 1H), 4.72 (s, 4H), 3.19 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.87 (s, 3H). MS (M+H)+: 632.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27]C=O)[C:25](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[SH:31][C:32]1[S:33][C:34]2[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:35]=2[N:36]=1.P(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)[Cl:54]>CN(C)C=O.C(N(CC)CC)C>[ClH:54].[NH2:27][C@@H:26]1[C:25](=[O:30])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])=[C:3]([CH2:2][S:31][C:32]3[S:33][C:34]4[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:35]=4[N:36]=3)[CH2:4][S:5][C@H:6]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: ClCCl
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nc4ccc([N+](=O)[O-])cc4s3)CS[C@H]12
Reaction time: 0.08 h

Procedure:
A solution of diphenylmethyl 3-bromomethyl-7β-formamidoceph-3-em-4-carboxylate, 1β-oxide (10.068g) and 2-mercapto-6-nitrobenzothiazole (4.244g) in dry N,N-dimethylformamide (125ml.) was stirred at 0°; a solution of triethylamine (3.2ml) in N,N-dimethylformamide (25ml) was added, dropwise, over 5 minutes, and stirring continued for a further 2 hours, during which time the temperature was allowed to rise to ca. 23°. The solvent was removed at 40°(2mm.); the residue was partitioned between methylene dichloride (300ml) and water (300ml), and the organic phase washed with 2N-hydrochloric acid, water, and brine and dried and evaporated to a foam (14.35g). A solution of this foam in dry methylene dichloride (200ml) was stirred at -20°, a solution of phosphorus tribromide (2.5ml, ca 1.5 equiv.) in methylene dichloride (25 ml) was added, dropwise, over 5 minutes, and stirring continued for a further 30 minutes at -10 to -15°. The resulting solution was stirred for 30 minutes with saturated sodium bicarbonate (250ml); the organic phase was separated, and washed with saturated sodium bicarbonate and brine and treated with some charcoal. The suspension was filtered through a kieselguhr pad, and the filtrate dried and evaporated to a foam (10.71g). A suspension of this foam in methanol (200ml) was stirred at 0°; phosphorus oxychloride (3.66 ml - 2 equivs.) was added, over 2 minutes, and stirring continued for a further 2 hours at ca. 23°, during which time the solid all dissolved. The solvent was evaporated off; ethyl acetate (100ml) was added, and the resulting suspension evaporated to dryness in vacuo. The residual gum was dissolved in methylene dichloride (100ml); the solution was stirred at 0° and ether (300 ml) was added, over 5 minutes. The precipitate was filtered off, and washed with ether (100 ml), and dried in vacuo to give the hydrochloride as pale-yellow flakes (9.744g, 78%); [α]D23 - 94° (c, 1.0, DMSO); λmax. (EtOH) 328nm. (ε 13,400); τ (DMS0-d6) values include 4.72 (6H and 7-H), 5.10 and 5.57 (3-CH2, q, J 14 Hz.), and 6.10 (2 CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Yield: 68 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 68%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.29 (m, 4H), 3.75-3.79 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 6.07-6.11 (m, 3H), 7.14 (s, 1H), 7.27-7.28 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:18])=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH3:16])[CH:12]=[C:11]([CH3:17])[CH:10]=2)=O)C.C1(C)C=CC=CC=1.CO.[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:18][C:7]1[C:6]([CH2:4][OH:3])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([CH3:17])=[CH:12][C:13]=2[CH3:16])[N:8]=1
Reactant: CCOC(=O)c1cc2c(C)cc(C)cc2nc1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2cc(CO)c(C)nc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,5,7-trimethylquinoline-3-carboxylic acid ethyl ester (50 mg, 0.206 mmol) in DCM (1.7 ml) at −78° C. was added DIBAI-H 1M in Toluene (29.2 mg, 0.206 mmol). Reaction mixture was stirred 1 h at −78° C. Methanol (1 ml) was added to quench the reaction at −78° C. Mixture was then warmed up to 23° C. Sat. potassium/sodium tartrate solution (Rochelle's salt, 2 ml) was added and mixture was stirred 30 min at RT. Solid was filtered off and filtrate was extracted twice with DCM. Combined organic layer was washed with sat. NaHCO3 solution, brine, dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.113 min, MS (Method V) [M+H]+=202.1
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20]>CN(C)C=O.O>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
Sodium hydride (1.51 g, 62.92 mmol, 2.00 equiv) was added in small portions to a solution of phenol (3.25 g, 34.53 mmol, 1.10 equiv) in N,N-dimethylformamide (50 mL) maintained under nitrogen at 0-5° C. After stirring for 30 min at 0-5° C., 1,2-difluoro-4-nitrobenzene (5 g, 31.43 mmol, 1.00 equiv) was added. The reaction mixture was stirred overnight at room temperature and then diluted with 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×150 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-2% ethyl acetate in petroleum ether to afford 3.2 g (44%) of 2-fluoro-4-nitro-1-phenoxybenzene as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.46-7.41 (m, 2H), 7.30-7.26 (m, 1H), 7.12-7.04 (m, 2H), 7.02-6.93 (m, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH3:1])=[N:3][NH:4]2)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1n[nH]c2cccc(O)c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2cccc(O[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a solution of 3-methyl-1H-indazol-4-ol (0.13 g, 0.90 mmol) in N,N-dimethylformamide (10 ml) was added imidazole (0.31 g, 4.52 mmol) and tert-butyldimethylchlorosilane (0.16 g, 1.04 mmol) at 0° C. Following stirring at room temperature for 12 hours and the addition of distilled water (10 ml), the reaction mixture was extracted three times with ethyl acetate, washed with distilled water and brine, dried over magnesium sulfate, filtered, and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give 0.21 g of 4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indazole (Yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:7]([C:28]#[N:29])[CH2:6]1)=[O:4].[CH3:30][I:31]>O1CCCC1>[I-:31].[C:28]([N:7]1[C@H:8]2[C@@H:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[C:11]([CH2:21][N+:22]2([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[NH:12]4)[CH2:19][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:29]
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]2N(C#N)C1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C[N+]5(C)CCOCC5)c(c34)C[C@H]2N(C#N)C1
Product: [I-]

Procedure:
1.13 g of 6-cyano-2-morpholinomethyl-8beta-ergoline-carboxylic acid methyl ester is dissolved in 45 ml of tetrahydrofuran and stirred with 2.4 ml of methyl iodide at room temperature overnight. The crystalline precipitate is filtered off, yield 1.26 g (82% of theory), [α]D =+9.7° (0.5% in DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.CCOC(C)=O.[NH2:36][NH2:37]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:36][NH2:37])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NNC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1

Procedure:
Methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoate from Step B (33 mg, 0.077 mmol) was suspended in 1 mL of EtOH and 0.5 mL of anhydrous hydrazine, and heated to reflux for 2 h. EtOAc was added and washed with water 3 times. The organics were dried (MgSO4), and concentrated to afford 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzohydrazide which was used with out further purification. LCMS: m/z 421.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])(CC)C.[CH2:17]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)[CH2:18][CH3:19].O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:35]=[CH:34][CH2:33][CH2:32][C@H:29]2[CH2:30][CH2:31][C@H:26]([C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24]3)[CH2:27][CH2:28]2)=[C:6]([F:10])[C:5]=1[F:11])[CH3:2]
Reactant: CCOc1cccc(F)c1F
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=Cc3ccc(OCC)c(F)c3F)CC2)CC1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
Under nitrogen gas stream, a solution of 30.7 g (194 mmol) of 1-ethoxy-2,3-difluorobenzene in 300 ml of THF was cooled down to −70° C., 194 ml of sec-butyl lithium (1.0M cyclohexane solution) was added by drops thereto while being maintained at the same temperature, and they were stirred at the same temperature for 2 hours. To this reaction mixture was added by drops a solution of 45.1 g (162 mmol) of the crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal obtained by the reaction in the fifth step in 450 ml of THF while being maintained at the same temperature, and stirred for 2 hours. Subsequently, they were raised up to −50° C. and stirred for 2 hours. The reaction mixture was added to 200 ml of water to terminate the reaction, the solvent was distilled off under a reduced pressure, the residue was extracted with 500 ml of toluene, and the organic layer was washed with 100 ml of water thrice, and then dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was removed by filtration, 2.83 g of p-toluenesulfonic acid monohydrate was added to the filtrate, and heated to reflux for 4 hours. The organic layer was washed with 200 ml of water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: mixed solvent of heptane/toluene=7/3) to obtain 50.2 g of a crude 1-ethoxy-2,3-difluoro-4-(4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butenyl)benzene.