Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=[C:4]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1ccc(C#CC2CC2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C#CC2CC2)nc1Cl
Yield: 64.5 %

Procedure:
The ester was hydrolyzed as follows: Ethyl 2-chloro-6-(2-cyclopropylethynyl)pyridine-3-carboxylate (0.7 g, 2.8 mmol) and lithium hydroxide (0.4 g, 16.86 mmol) were refluxed in a mixture of 30 mL MeOH and 10 mL water. The mixture was cooled and the methanol was removed in vacuo. The remaining solution was acidified to pH 2 with 1M HCl at 0° C. The precipitate was filtered and dried to give 0.4 g (57%) of the title compound. m/z=222.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: Fc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-fluorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 344.22 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:39]([C:36]4[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=4)=[O:40])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: COc1ncc(C(=O)O)cn1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Product: COc1ncc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)cn1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 563.2 (MH+, 1Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:7]=2[NH:6][C:5]1=[O:38].[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:7]4[N:6]([CH3:39])[C:5](=[O:38])[CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]=4[N:10]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (40 mg, 0.078 mmol) in DMF(1 ml) was added potassium carbonate (32 mg) and methyl iodide (13.2 mg, 0.093 mml) were added. The reaction mixture was stirred at room temperature for 4 h.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:55]=1[CH2:61][C:62](O)=[O:63]>CN(C=O)C.CO.C(Cl)Cl>[F:53][C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:55]=1[CH2:61][C:62]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:63]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Nc1ncnc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred dark brownish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (360 mg, 1.43 mmol) and HATU (597 mg, 1.57 mmol, 1.1 equiv) in 3 mL of DMF was added DIEA (274 uL, 1.57 mmol, 1.1 equiv). To this mixture was added (2,5-difluorophenyl)acetic acid portionwise (246 mg total, 1.43 mmol, 1 equiv) over a 1 h period. The mixture was stirred for another 2 h and then added to 50 mL of ice water. The resulting suspension was filtered. The brownish cake was washed with water (2×10 mL) and then sucked under house vacuum for 20 h to give crude product (760 mg). This material was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A to 55% A (A was a mixture of 3200 mL DCM, 800 mL of MeOH and 80 mL of conc NH4OH). The desired product eluted from 29-32%. Each fraction was checked by LCMS and the 2 pure fractions were combined with impure product from a previous run and concentrated in vacuo. The residue was dissolved in 10% MeOH in CHCl3, and filtered The filtrate was concentrated in vacuo. The residue was taken up in 1.5 mL of CHCl3, and MTBE (1 mL) and hexane (7 mL) were added to give a suspension. Which was filtered. The cake was washed with hexane (2×4 mL) and then dried under vacuum at 65° C. for 18 h to afford 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[2, 3-d]pyrimidin-4-amine (295 mg) as an off-white solid. NMR, LCMS and HPLC showed this sample was pure. LC-MS (ES) m/z=407 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.6 Hz, 2H), 3.96 (s, 3H), 4.30 (t, J=8.5 Hz, 2H), 7.13-7.28 (m, 3H), 7.30 (d, J=9.1 Hz, 1H), 7.40 (s, 1H), 7.93 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), NH2 protons are not visible.
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[C:20]([C:25](Cl)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])/[CH:3]=[C:4](/[C:25](=[O:26])[C:20]1[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1ncccc1Cl
Reactant: CCOC(=O)/C=C/N(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1Cl
Temperature: 83 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
To a light yellow solution of (E)-ethyl 3-(dimethylamino)acrylate (1.72 g, 12.0 mmol) in toluene (20 mL) was added triethylamine (1.21 g, 1.67 mL, 12.0 mmol) at room temperature. To this, a solution of 3-chloropicolinoyl chloride (34) (1.76 g, 10 mmol) in toluene (5 mL, heated to dissolve) was added. Then, the resulting dark brown solution was heated to 83° C. and stirred for 12 h at this temperature. During this period, it turned to a dark brown solution. Then, the heating was stopped and the dark brown mixture was filtered off and the solids were washed with ethyl acetate. The brown ethyl acetate solution was washed with water which was diluted with 1.0N HCl. The acidic aqueous layer was extracted one more time with ethyl acetate and the combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave only 1.6 g of crude brown mixture. Then, the acidic aqueous layer was extracted with dichloromethane (2×100 mL) and then the aqueous layer was neutralized with a saturated sodium bicarbonate solution and then extracted one more time with dichloromethane. The combined dichloromethane extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave another 1.2 g of dark drown oil which was combined with the first brown residue and the mixture was purified using an ISCO (120 g) column, eluting with ethyl acetate in hexanes (0 to 100%) and then 10% methanol in dichloromethane. The pure fractions were combined and the solvent was removed under vacuum to obtain (Z)-ethyl 3-(dimethylamino)-2-(3-chloropicolinoyl)acrylate (35) (1.16 g, 41% yield) as a dark brown oil.
Reaction SMILES: [C:1]([O:3][CH2:4][CH3:5])#[CH:2].B.C1COCC1.C(OC=CB(C=COCC)C=COCC)C.Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH3:36])[N:30]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[Na+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][CH:4]=[CH:5][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH3:36])[N:30]=1)[CH3:2]
Reactant: CSc1nccc(Cl)n1
Reactant: C#COCC
Agent: [Pd+2]
Agent: B
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC=Cc1ccnc(SC)n1
Temperature: 0 °C

Procedure:
Ethyl ethynyl ether (2.50 g, 35.7 mmol) was dissolved in 50 mL anhydrous THF under N2. The solution was cooled to 0° C. and BH3-THF (1.0 M in THF, 11.9 mL, 11.9 mmol) was added drop-wise. The reaction was allowed to warm to RT and after 2 h the tris-(2-ethoxy-vinyl)borane that was generated was used in the next step. A flame dried flask under N2 was charged with 4-chloro-2-(methylthio)pyrimidine (0.200 g, 1.25 mmol), Pd(OAc)2 (0.003 g, 0.01 mmol), PPh3 (0.010 g, 0.040 mmol), NaOH (0.149 g, 3.73 mmol). Anhydrous THF, 2 mL, was added followed by the addition of 0.700 mL (0.50 mmol) of the solution of tris-(2-ethoxy-vinyl)borane generated above. The reaction was heated at reflux for 16 h, then was cooled to RT and quenched with sat NaHCO3 (aq). The mixture was extracted 3× with EtOAc and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The product was purified to moderate purity by flash column chromatography and used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@H:26]3[CH2:29][C@H:28]([CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1>N1CCCC1>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:26]3[CH2:27][C@H:28]([CH2:30][N:8]4[CH2:9][CH2:10][CH2:3][CH2:4]4)[CH2:29]3)[C:9]=2[CH3:25])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3c(C)c(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1
Solvent: C1CCNC1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@H](CN2CCCC2)C1

Procedure:
0.335 g (0.589 mmol) trans-toluene-4-sulfonic acid 3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester of Example 106 in 3.6 ml pyrrolidine are stirred at RT for 3.5 h (Thin Layer Chromatography and HPLC control). The excess reagent is evaporated on a rotavap and the residue purified by chromatography (solvent: ethyl acetate-MeOH-aqu. NH3 (33%) 95:5:1). The compound is crystallized from diethylether. Analytical HPLC: tR=9.09 min (Grad 1); mp: 136-140° C.; ES-MS: m/eo=468.3; NMR (DMSO-d6; not all signals reported): 8.10/s (1H), 7.25-7.5/several m's (6H), 7.02/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.06/m (1H); 2.22/s (3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl.C1COCC1.CN(C=O)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1I
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
3-Iodo-4-methyl-benzoic acid (1.0 g, 3.96 mmol) in dry CH2Cl2:THF 1:1 (200 mL) was treated with oxalyl chloride (1 mL, 11.9 mmol) and several drops of DMF. The mixture was heated at 65° C. for 30 minutes, cooled to ambient temperature, and concentrated under reduced pressure to provide a light yellow solid. The obtained solid in THF (200 mL) was treated with LiAlH(OtBu)3 (4.1 mL, 4.1 mmol) via syringe at −78° C. After 30 minutes at −78° C., a saturated solution of Rochelle's salt was added and the mixture was allowed to warm to ambient temperature. The organic layer was washed in succession with 1 NHCl, saturated NaHCO3, brine, dried over Na2SO4, and the solvent removed under reduced pressure. The resulting residue was purified by flash chromatography using hexanes:EtOAc (4:1) as eluent to provide 3-iodo-4-methylbenzaldehyde as a white solid (300 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][CH:14]=3)(=[O:30])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc2ncc(S(=O)c3ccc(C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc2ncc(S(=O)(=O)c3ccc(C)cc3)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−)-3-(4-methylphenylsulfinyl)-5-methoxyquinoline (2.97 g, 10 mmol) prepared in stage B of example 10 in CH2Cl2 is added m-CPBA (2.13 g, 80%, 10 mmol). The solution is stirred at room temperature for 12 hours. A solution of 1M NaOH is added. After extraction of the aqueous phase with CH2Cl2, the combined organic layers are dried (MgSO4) and the solvent evaporated giving the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][CH2:25][NH:26][CH2:18][C:16]2[CH:15]=[CH:14][C:3]([O:4][C:5]3[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=3)=[C:2]([F:1])[CH:17]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2F)cn1
Reaction time: 8 h
Yield: 44 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 3,4-dichlorophenethylamine (0.320 g, 1.68 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give the title compound (0.293 g, 44%): TOF MS ES+ 435.1 (M+H)+, HRMS calcd for C20H18N4O2FCl2 435.0791 (M+H)+, found 435.0815, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.8 min, 100% purity.
Reaction SMILES: Cl[C:2]1[CH:7]=[N+:6]([O-:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH-].[NH4+:12]>>[NH2:12][C:2]1[CH:7]=[N+:6]([O-:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1c[n+]([O-])cc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Product: COc1c[n+]([O-])cc(N)n1

Procedure:
2-Chloro-6-methoxypyrazine 4-oxide is treated with an excess of ammonium hydroxide in an autoclave at 150° C. for 14 hours. The reaction mixture is cooled and evaporated to dryness to give the crude product which may be used in the next step as is.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=O.S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+].NC(N)=O.[N-]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH:6]1[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]2[C:2](=[N+:1]([O-:16])[O:14][N:12]=2)[CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: [O-][n+]1onc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 103 grams (0.5 mole) of 4-amino-3-nitro-benzotrifluoride, 750 ml. of acetic acid and 385 ml. of concentrated sulfuric acid is cooled in an ice-bath with sufficient stirring. Sodium nitrite (38 grams, 0.55 moles) is added portionwise at such a rate that the reaction temperature does not exceed 5° C. After addition is complete, 38 grams of urea is added, and with vigoroug stirring 32.5 grams of sodium azide is then added. Stirring is continued for 20 minutes, then the reaction mixture is poured into 4 liters of ice and water. The crude product, 4-azido-3-nitrobenzotrifluoride is extracted from the aqueous mixture with chloroform. The extract is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to furnish an oily-residue which is taken up in 800 ml. of toluene. The toluene solution is heated under reflux for 18 hours behind a shatter-proof shield. After cooling to room temperature, the solvent is evaporated and the residue is distilled under reduced pressure. The fraction boiling at 105°-108° C. (16 ml.) is considered to be sufficiently pure 5-trifluoromethylbenzofuroxan; yield, 62.3 (60 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]1[CH2:13][CH2:14][NH:15][CH2:16][CH:7]1[C:6](=[O:17])[NH:5]2.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:18][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH:7]1[C:6](=[O:17])[NH:5]2
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNCC12
Reactant: C=Cc1ccncc1
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCN(CCc3ccncc3)CC12

Procedure:
Treatment of 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one (3 g.) with 5.4 g. of 4-vinylpyridine in the manner described in Example 1 gave 2.2 g. of the title compound as the dihydrochloride salt, m.p. 266°-269° C. (dec.).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4-c4ccccc4)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4-c4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A mixture of methyl 4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoate (235 mg, 0.461 mmol), prepared in the previous step, and 1 N NaOH (692 μL, 0.692 mmol) in 30 mL of THF plus 30 mL of methanol plus 5 mL of water was refluxed under nitrogen for 7 h. The reaction was filtered, cooled to room temperature, acidified by the addition of 2.5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (225 mg, 99%) as a white solid, mp 309–310° C. Elemental Analysis for C34H25NO3.0.05 C4H8O.0.19 H2O Calc'd: C, 81.73; H, 5.17; N, 2.79. Found: C, 81.94; H, 5.02; N, 2.65.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[CH:8]([OH:11])[CH2:9][CH3:10].[H-].[Na+]>>[CH2:1]([O:11][CH:8]([C:7]1[CH:6]=[C:5]([CH3:12])[N:4]=[C:3]([O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:2]=1[CH3:1])[CH2:9][CH3:10])[CH2:2][CH2:7][CH3:6]
Reactant: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Agent: [H-]
Agent: [Na+]
Product: CCCCOC(CC)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared by reacting of 1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol with sodium hydride, followed by quenching with butyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:20]([CH3:32])=[C:19]([CH3:33])[C:18]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]O)[CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:40][C:36]3[CH:35]=[C:34]([C:18]4[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])=[C:20]([CH3:32])[C:19]=4[CH3:33])[CH:39]=[CH:38][CH:37]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(C)c(OCCCS(C)(=O)=O)c(C)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,3′,5′,6′-tetramethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.377 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20) to give the title compound (0.462 g, yield 82%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:21]([I:22])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:24]1[CH2:27][CH:26]([CH2:28][OH:29])[CH2:25]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([I:22])[C:2]([N:24]3[CH2:27][CH:26]([CH2:28][OH:29])[CH2:25]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: OCC1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 88.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3) and 3-azetidinemethanol hydrochloride to afford a beige solid. HPLC (Condition 7) tR=6.5 min, UPLC-MS (Condition 8) tR=1.1 min, m/z=510.0/512.0 [M+H]+.