Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=O)[N:9](C)[CH2:10][CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([NH:23][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])[CH:21]=[CH:22][C:13]2=3)C=CC=CC=1.[OH-].[Na+].O>C(O)C.CO.C(Cl)Cl>[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:13]1=2
Reactant: CN(CCN1CCCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CNCCN1CCCCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 1 h
Yield: 40.6 %

Procedure:
A solution of phenyl-methyl(2-(7-(thiophene-2-carboximidamido)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethyl)carbamate (200 mg, 0.45 mmol) in 12 mL ethanol was treated with NaOH (178 mg, 4.46 mmol) followed by H2O (5 mL). The mixture was then heated at reflux for 6 hours. A TLC analysis indicated that starting material is present. At this moment, NaOH (90 mg) was added and heating was continued for 1 hour. The solution was concentrated to about 5 mL and partitioned between CH2Cl2 (100 mL) and brine (20 mL). After extraction, the organic layer was separated and the aqueous layer was extracted once more with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a yellow oil. This residue was subjected to flash chromatography on silica gel using 2.5-10% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid (60 mg, 40.5%). 1H-NMR (DMSO-d6) δ 7.70 (d, J=3.3 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.91-6.88 (m, 1H), 6.64-6.62 (m, 2H), 6.33-6.31 (m, 2H), 3.14 (t, J=6.3 Hz, 2H), 2.85-2.70 (m, 2H), 2.77-2.61 (m, 4H), 2.31 (s, 3H), 1.67-1.62 (m, 2H), 1.50-1.46 (m, 2H). MS (EI): 329.2 (M+1). ESI-HRMS calculated for C18H25N4S (MH+): 329.1794, Observed: 329.1802.
Reaction SMILES: Cl.[C:2]1([CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.O>CN(C)C=O>[C:2]1([CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccccc1C1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a stirring solution of 4.2 g of 4-(2-toluyl)piperidine hydrochloride and 4.0 g of triethylamine in 150 ml of dimethylformamide is added 3.8 g of 3-(2-bromoethyl)indole. The resulting solution is stirred at ambient temperature for 70 hours and stirring is continued while 500 ml of water are added dropwise. An oil appears which is extracted from the solution with chloroform, the combined chloroform extracts are dried and the excess chloroform is removed, leaving an oil which crystallizes upon standing. The solid product is recrystallized from cyclohexane and then twice from an ethanol-water mixture to give flakes, mp 111°-112° C., 3-{2-[4-(2-toluyl)piperidyl]ethyl}indole.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(COC(C)(C)C([NH:23][OH:24])=O)=N1)(=O)C1C=CC=CC=1.[CH2:27]([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][O:44][CH2:45][CH2:46][O:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][O:44][CH2:45][CH2:46][O:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:23][OH:24])=[O:50])=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(OCc1nn(C(=O)c2ccccc2)c2ccccc12)C(=O)NO
Reactant: CC(C)(OCCOCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Product: CC(C)(OCCOCc1nn(Cc2ccccc2)c2ccccc12)C(=O)NO

Procedure:
The product was obtained with the method described for the preparation of compound 34e), using 2-{2-[(1-benzyl-1H-indazol-3-yl)methoxy]ethoxy}-2-methylpropanoic acid as starting material.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 250-mL round-bottom flask was placed a mixture of 4-bromoaniline (6.90 g, 40.1 mmol), triethylamine (16.8 g, 166 mmol), 4-dimethylaminopyridine (200 mg, 1.64 mmol), and 2-phenylacetyl chloride (6.50 g, 42.1 mmol) in dichloromethane (150 mL). The resulting mixture was stirred for 12 hours at 25° C. The reaction was then quenched by the addition of 50 mL of water. The organic layer was separated, and the aqueous layer was extracted with 2×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel column, 100:1 to 10:1 CH2Cl2/MeOH) to provide the title compound as a light yellow solid.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:9]([NH:11][C@H:12]([C:28]([NH:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.N1CCCCC1>ClCl>[NH2:1][C@@H:2]([C:9]([NH:11][C@H:12]([C:28]([NH:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: O=C(N[C@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCc1ccccc1)OCC1c2ccccc2-c2ccccc21
Agent: ClCl
Solvent: C1CCNCC1
Product: N[C@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCc1ccccc1
Reaction time: 2 h

Procedure:
Fmoc-D-His-Tyr(OBn)-CONH(CH2)2Ph (0.6 g, 0.8 mmol) in CH2 Cl2 (5 mL) was treated with piperdine (0.14 g, 1.6 mmol). The resulting mixture was stirred 2 hours before concentrating in vacuo and purifying the resulting by flash chromatography (SiO2, CHCl3 :MeOH eluent) to give D-His-Tyr(OBn)-CONH(CH2)2Ph. The foam was dissolved in CH2C2 (5 mL) and treated with 4-phenoxyphenyl isocyanate (0.05 g, 0.23 mmol). The resulting mixture was stirred 1 hour at room temperature, concentrated in vacuo, and purified the resulting oil by flash chromatography (SiO2, CHCl3 :MeOH eluent) to obtain (4-PhOPh)NHCO-D-His-Tyr(OBn)-CONH(CH2)2Ph as a foam; ES-MS 723 (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A 250 mL round bottom flask with was charged with 5-bromo-1H-indazole (25.00 g, 0.127 mol, 1.0 eq), and dichloromethane (100 mL). To the suspension was added dihydropyran (32.0 g, 0.381 mol, 3.0 eq) and a catalytic amount of pyridinium para-toluenesulfonate (3.19 g, 0.0127 mol, 0.10 eq). The mixture was stirred overnight, and in the morning was a clear solution. The methylene chloride was washed sequentially with saturated sodium bicarbonate, 10% citric acid, and brine, and was then evaporated. Chromatography of the residue on silica gel, eluting with EtOAc/heptane, gave the title compound as a colorless liquid (28.00 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[N:3]=1.[C:21](=[O:24])([O-])[O-:22].[Na+].[Na+]>CN(C)C=O.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>[O:22]1[C:9]2[CH:10]=[CH:11][C:12]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]4)[N:3]=3)=[CH:13][C:8]=2[O:24][CH2:21]1
Reactant: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1CCN(c2nc(-c3ccccc3)cc(-c3ccc4c(c3)OCO4)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound benzo[1,3]dioxo-5-yl boronic acid (0.14 g, 83 mmol), and compound 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol (90.2 g, 69 mmol), (PPh3)4Pd (31 mg, 0.03 mmol) and sodium carbonate (0.73 g, 69 mmol) in dimethylformamide (5 mL) was stirred for 1 hour at 25° C. and then for 12 hours at 80° C. under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C., diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were collected, combined, washed with water (10 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to give the desired compound.
Reaction SMILES: NC1C=C(C)C=CC=1[C:4](O)=[O:5].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[NH:12][C:4]([NH:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)=[O:5])=[O:21]
Reactant: Nc1nccs1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: COc1ccccc1C(=O)c1ccc(C)cc1N
Product: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nccs1
Yield: 70 %

Procedure:
(2-Amino-4-methyl-phenyl)-(2-methoxy-phenyl)-methanone (723 g, 30%) was prepared from 2-amino-4-methyl-benzoic acid (1.51 g, 10 mmol) following the general procedure S. 1-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-3-thiazol-2-yl-urea (129 mg, 70%) was prepared from (2-amino-4-methyl-phenyl)-(2-methoxy-phenyl)-methanone (121 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[CH2:34][O:33]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:34][CH:32]([OH:33])[C:31]([F:36])([F:35])[F:30])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: FC(F)(F)C1CO1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(O)C(F)(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Reaction time: 8 h

Procedure:
The mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol) and 2-(trifluoromethyl)oxirane (67.8 mg, 0.60 mmol) in 2 mL of DMF was stirred overnight. The reaction mixture was purified by preparative RP-HPLC to afford 3-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol. ESMS m/z 528.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[C:15]([Si:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)Cl)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 113.7 %

Procedure:
A solution of methyl 2,2-dimethyl-3-hydroxypropionate (5.0 g, 37.8 mmol) in DMF (75 mL) was cooled to 0° C. and treated with imidazole (3.86 g, 56.7 mmol) then tert-butyl diphenylchlorosilane (11.8 mL, 45.4 mmol). The mixture was stirred at RT for 22 h then concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated in vacuo to give the title compound as a golden oil (15.93 g, quant.). LCMS (Method 3): Rt 5.32 min, m/z 393.3 [M+Na+].
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C.CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[NH:1][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3N)c2cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)cc3Nc3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
4-(2-Amino-4-methylphenoxy)-6,7-dimethoxyquinoline (52 mg) was dissolved in triethylamine/N,N-dimethylformamide (0.5 ml/2.5 ml), and phenylboronic acid (100 mg) and copper acetate (250 mg) were added to the solution which was then stirred at room temperature overnight. The reaction solution was filtered, and the solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. Next, the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (50 mg, yield 76%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([Cl:13])=[O:10]
Reactant: O=C(O)C=Cc1cccs1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1cccs1

Procedure:
65 ml of benzene was added to 10 grams of 3-(2-thienyl)acrylic acid. 7.8 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[CH:12][C:8]=1[C:9]([O:11][CH3:18])=[O:10]
Reactant: Cc1cc(Br)c(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(C)cc1Br

Procedure:
Molecules of the present invention can be synthesized using well-known organic synthesis methods. FIG. 8 shows a method for synthesizing a molecule belonging to the subclass shown in FIG. 6 according to one embodiment of the present invention. A detailed description of the organic synthesis is described below in an experimental subsection called “Synthesis of 1,4-bis[3′,5′-di-tert-butylphenylethynyl]-5-methyl-2-methoxycarbonylbenzene.” The organic synthesis includes adding nitric acid and water to a solution of 2,5-dibromo-p-xylene 802, which is refluxed to obtain in solution 2,5-dibromo-4-methylbenzoic acid 804. Methanol and concentrated sulfuric acid are added to the solution of 2,5-dibromo-4-methylbenzoic acid 804, which is refluxed to obtain a solution of methyl 2,5-dibromo-4-methylbenzoate 806. In a separate part of the synthesis, trifluoromethanesulfonic anhydride and pyridine are added to a solution of 3,5-di-tert-butylphenol 808 and the solution is warmed to room temperature to obtain 3,5-di-tert-butylphenyl triflate 810. A solution of 3,5-di-tert-butylphenyl triflate 810, PdCl2, (PPH3)2, CuI, tetrabutylammonium iodide, and trimethylsilylacetylene are stirred to obtain 1-[3′,5′-di-tert-butylphenyl-2-trimethylsilylacetylene 812. Combining 1-[3′,5′-di-tert-butylphenyl-2-trimethylsilylacetylene 812, methyl 2,5-dibromo-4-methylbenzoate 806, PdCl2, (PPH3)2, CuI, triethylamine, tetrahydrofuran, and tetrabutylammonium fluoride and stirring at room temperature yields the desired molecule 1,4-bis[3′,5′-di-tert-butylphenylethynyl]-5-methyl-2-methoxycarbonylbenzene 814.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.1 mmol) in EtOH (70 ml) and H2O (14 ml) was added iron (11.7 g, 211 mmol) and NH4Cl (6.76 g, 126 mmol) at room temperature. The mixture was refluxed for 1 hour, and then cooled to room temperature, filtered through a Celite pad and washed with EtOH. The filtrate was concentrated in vacuo. The residue was treated with saturated aq. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (Hexane:EtOAc=3:1) to give 5-bromo-2-chloropyridin-3-amine (7.93 g, 91%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.89 (2H, s), 7.30 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][CH:3]=1.B.[OH-].[Na+].[Cl-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1
Reactant: Nc1cccc(C(=O)O)n1
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
A mixture of 6-aminopyridine-2-carboxylic acid (5.0 g.) and a 1.35M solution of borane in tetrahydrofuran (100 ml.) was stirred under argon at reflux for 48 hours. The mixture was cooled and treated with 2N NaOH (50 ml.) and the mixture stirred at room temperature for 18 hours. The aqueous phase was saturated with sodium chloride and the organic phase separated. The aqueous phase was extracted twice with ethyl acetate and the ethyl acetate extracts combined with the tetrahydrofuran solution and the whole evaporated to dryness. The residue was dissolved in ethyl acetate (100 ml.) and the solution washed with saturated aqueous sodium chloride solution (5 ml.) and then dried and evaporated to dryness to give crude 2-amino-6-hydroxymethylpyridine (2.3 g.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])[C:5](O)=[O:6].CN(C)C=O.C(Cl)(=O)C([Cl:32])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])[C:5]([Cl:32])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(=O)O)c1ccccc1COc1ccc(Cl)cc1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1ccccc1COc1ccc(Cl)cc1C
Reaction time: 1 h

Procedure:
To a mixture of 52.24 g (0.150 mol, E/Z=3.5/96.5) of α-methoxyimino-2-(4-chloro-2-methylphenoxymethyl)phenylacetic acid produced in accordance with Example 5-(2), 0.57 g (0.0078 mol) of dimethylformamide and 203 g of toluene was added dropwise 25.9 g (0.204 mol) of oxalyl chloride over 3 hours while keeping at 60°-65° C., and the reaction was subsequently allowed to proceed at the same temperature for 1 hours and then 80° C. for 2 hours, which afforded 265 g of a toluene solution of α-methoxyimino-2-(4-chloro-2-methylphenoxymethyl)phenylacetyl chloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:30][C:31](=[O:43])[C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[C:11]([N:13]1[CH2:17][CH2:16][C:15]2([CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][N:19]([CH3:28])[C:18]2=[O:29])[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:35][C:32]([CH3:34])([CH3:33])[C:31]([NH:30][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:17][CH2:16][C:15]2([CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][N:19]([CH3:28])[C:18]2=[O:29])[CH2:14]1)=[O:12])=[O:43]
Reactant: CN1CC(c2ccccc2)C2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of tert-butyl 1-((2R)-3-(benzyloxy)-1-(7-methyl-6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonan-2-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (step 3) (206.5 mg) in DCM (4 mL) was treated with TFA (537 uL, 6.97 mmol). The reaction mixture was stirred at room temperature for 2 days. A further portion of TFA (2 ml) was added and stirring continued for 20 minutes. The mixture was concentrated in vacuo to afford a colourless oil. The oil was dissolved in MeOH and applied to a 10 g pre-wetted (MeOH) SCX-2 cartridge. The column was washed with MeOH (70 mL) and the product was eluted with 2M NH3 in MeOH (70 mL). The clean fractions were concentrated in vacuo to afford a colourless oil. The oil was further purified by mass-directed LC-MS to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])[O:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][S:18]([CH3:17])(=[O:20])=[O:19])[O:5]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 5 mmol) in pyridine (20 mL) was added methanesulfonyl chloride (627 mg, 5.5 mmol) and the mixture stirred at rt for 24 hours. The solvent was then removed under reduced pressure, and the resulting residue redissolved in DCM (200 mL), washed with 1 N HCl (1×100 mL) and 20% NaHCO3 (1×100 mL). The organic layer was then isolated, dried (Na2SO4) and concentrated to dryness. The crude product was purified by crystallization from DCM/hexanes to give the title compound (700 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.82-7.77 (m, 1H), 7.59 (d, J=8.2, 1H), 7.51-7.43 (m, 1H), 7.17-7.10 (m, 1H), 2.95 (s, 3H), 1.37 (s, 12H).