Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][NH:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][N:28]=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C(O)(C)C>[Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:25]2[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][N:28]=[CH:27][C:26]=2[CH3:34])[CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Cc1cncc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cncc([N+](=O)[O-])c1N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 48 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (23 mg, 0.067 mmol, Example 26, Step 7), 4-chloro-3-methyl-5-nitropyridine (from ACES Pharma, 16 mg, 0.096 mmol), and triethylamine (37 μL, 0.27 mmol) in isopropyl alcohol (0.60 mL) was heated at 75° C. in a sealed vial for 16 h. Another portion of 4-chloro-3-methyl-5-nitropyridine (19 mg) was added and stirring was continued for 2 days at 100° C. The crude reaction mixture was purified by flash chromatography (24 g silica gel column, eluting with 0-100% EtOAc/hexanes) to afford the sub-title compound (12 mg, 37% yield). LCMS (ESI) calc. for C23H41N4O5Si [M+H]+: m/z=481.3. found 481.3.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isatin (2.5 g, 0.017 mol) in anhydrous DMF (50 ml) was cooled to 0° C. under a nitrogen atmosphere and treated with sodium hydride (0.5 g, 1.2 equivalents). A purple solution was formed which was stirred at 0° C. for 30 minutes and then warmed to room temperature. 4-Bromoanisole (2.13 ml, 1 equivalent) was added followed by copper iodide (6.46 g, 2 equivalents). The reaction was heated in an oil-bath at 145° C. for 7 hours. The reaction was then cooled to room temperature and diluted with an equal volume of ethyl acetate. This suspension was filtered and the filtrate was evaporated to dryness. TLC (1:4, ethyl acetate:hexanes) indicated a very clean reaction; Rf (product)=0.5. The crude material was used as such for the next reaction.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl.[OH2:6].[N+]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O>>[C:12]([C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:12][CH:11]=1)(=[O:6])[CH2:11][CH2:10][CH2:15][CH3:14]
Reactant: O
Reactant: O=[N+]([O-])c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
560 Gram of granular anhydrous aluminum chloride and 1 l of nitrobenzene were introduced into a 5 l three neck flask, and stirred under water-cooling to give a solution. A solution of 600 g of diphenyl and 482.5 g of n-valeric acid chloride dissolved in 1 l of nitrobenzene (prepared in advance) was dropwise added into said three neck flask over 2 hours. After the addition, the resulting mixture was stirred for one hour as it was. Thereafter it was stirred at 40°-45° C for 2 hours, cooled to room temperature, poured cautiously into a mixed solution of 1.3 l of conc. hydrochloric acid and 1.5 l of water for decomposing the catalyst, and cooled to 20° C. Precipitated crystal was separated by filtration. Nitrobenzene was distilled off from nitrobenzene layer by distillation under a reduced pressure to give an additional crystal. Both the crystals were recrystallized from ethanol to give 881 g of crystal of 4-n-pentanoylbiphenyl (m.p. 79°-79.5° C) (yield: 95% based on biphenyl).
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[C:10](=[S:14])([NH2:13])[CH2:11][CH3:12]>C(O)C>[CH2:11]([C:10]1[S:14][C:2]([CH3:9])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:13]=1)[CH3:12]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: CCC(N)=S
Solvent: CCO
Product: CCc1nc(C(=O)OC)c(C)s1
Yield: 52.7 %

Procedure:
A mixture of methyl 3-bromo-2-oxobutanoate (16.2 g), propanethioamide (7.4 g) and ethanol (150 mL) was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:4, v/v) to give methyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate as a yellow oil (8.1 g, yield 53%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:14][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([CH2:8][O:9][CH3:10])[N:4]=1)=[O:13]
Reactant: COCc1ccc(Br)c(C(=O)O)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COCc1ccc(Br)c(C(=O)OC)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 3-bromo-6-methoxymethyl-pyridine-2-carboxylic acid (200 mg, 0.81 mmol) in benzene (4 ml) and MeOH (1 ml) was slowly added trimethylsilyl-diazomethane (0.41 ml, 0.81 mmol) at ambient temperature, and the reaction mixture was stirred for 2 hours. The solvents were removed and the residue was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 158 mg (75%) of the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=[C:13]([Cl:20])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=[C:13]([Cl:20])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([CH:6]=1)[CH:33]=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C=O)c2)c(Cl)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of the title compound of Step B (410 mg, 1.31 mmol), hexamethylenetetramine (256 mg, 2.0 mmol) and trifluoroacetic acid (2.5 ml) under nitrogen was heated to 75° C. and stirred for about three hours. The solution was concentrated in vacuo to give a yellow viscous oil. Water (20 ml) was added to the yellow oil and the mixture was stirred for about 30 minutes at room temperature. The aqueous solution was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2×50 ml), brine (50 ml), dried, filtered and concentrated to give the title compound (440 mg ) as a crude product which was used in the next step without further purification. NMR (400 MHz, CDCl3) δ10.36 (s, 1H), 7.33 (s, 2H), 7.11-7.16 (m, 2H), 6.93 (d, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)([CH3:36])[CH3:35]>>[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1)([CH3:36])[CH3:35]
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccccc1OC(C)C)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 86 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-isopropoxyphenyl boronic acid. The title compound (147 mg) was obtained as a white solid, (yield=86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16](O)=[O:17])[CH:5]=[CH:4][C:3]1=2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:35])=O>ClCCl>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([Cl:35])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)O)ccc21
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Reaction time: 1 h

Procedure:
A solution of 2.6 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acrylic acid in 50 ml of anhydrous dichloromethane is introduced into a round-bottomed flask, 2 ml (10 mmol) of dicyclohexylamine are added and the mixture is stirred for one hour. 800 μl (10 mmol) of thionyl chloride are then added and the mixture is stirred for one hour. The mixture is evaporated to dryness, the residue is taken up in anhydrous ethyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 2.8 g (100%) of the crude acid chloride are collected, which product will be used subsequently in the synthesis without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][N:5]([CH3:17])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CI
Reactant: CC(C)(C)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of tert-butyl 3,3-dimethylbutylcarbamate (1.72 g, 8.56 mmol) in dry DMF (20 mL) was portionwise added 60% NaH in mineral oil (685 mg, 17.12 mmol) under a N2 atmosphere. After 30 min, MeI (2.68 mL, 42.8 mmol) was added dropwise with ice cooling. The mixture was stirred at room temperature for 2 d, poured in ice-H2O and extracted with Et2O (30 mL). The organic layer was dried (Na2SO4) and concentrated to yield the desired product (1.43 g, 63%, 80% purity) as a colourless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[N:2]1
Reactant: OCCc1noc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1noc2ccccc12
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 2-benzo[d]isoxazol-3-yl-ethanol (0.537 g, 3.29 mmol, from step (i) above ) and triethylamine (0.55 mL, 3.95 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.31 mL, 3.95 mmol) at 0° C. The reaction mixture was stirred for 1 hour and was then extracted with water (2×20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, which afforded 818 mg (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7](O)[C:6]=2[CH:16]=1.P(Br)(Br)[Br:18].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[Br:18][CH:7]1[C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2=[CH:12][CH:13]=[CH:14][N:9]2[CH2:8]1
Reactant: OC1Cn2cccc2Sc2ccc(F)cc21
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc2c(c1)C(Br)Cn1cccc1S2
Yield: 48 %

Procedure:
To a solution of 24c (0.17 g 0.71 mmol) in dry ethyl ether (3 ml) was added dropwise a solution of phosphorus tribromide (μL 33.5, 0.36 mmol) in dry ethyl ether (0.7 ml); the reaction mixture was refluxed for 2 hours under argon atmosphere. After cooling to room temperature dry ethanol (μL 143) was added and the resulting solution was heated at reflux for 1 hour. Then 4 ml of aqueous sodium carbonate was added; the organic phase was separated, dried and evaporated. The crude product was chromatographed (50% petroleum ether 40-60° in dichloromethane) to give 0.103 g of pure 25c (48% yield). 1H NMR (CDCl3) δ7.35-7.16 (m, 2H); 6.92-6.82 (m, 2H); 6.39-6.37 (m, 1H); 6.13-6.09 (m, 1H); 5.69-5.64 (m, 1H); 5.10-5.01 (dd, 1H, J=14.57, 2.65 Hz); 4.70-4.59 (dd, 1H, J=14.88, 7.05 Hz).
Reaction SMILES: CC([O-])=O.[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1.Cl.[OH:19][NH2:20]>O.CCO>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[N:20][OH:19])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCOc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
NaOAc (3.78 g, 46.2 mmol) in H2O (30 mL) was added to a soln of 7-bromo 4-chromanone (3.5 g, 15.4 mmol) and hydroxyl-amine hydrochloride (1.75 g, 23.1 mmol) in EtOH (70 ml). The reaction was heated at reflux for 2 h, cooled to room temperature, and concentrated. The residue was diluted with H2O and a precipitate was filtered to give 7-bromochroman-4-one oxime obtained as the needle like crystals 3.5 g (98%). LCMS 244 (M+2H) RT=1.7 min (Condition 2); 1H NMR (DMSO-d6) 11.37 (s, OH, 1H), 7.76-7.70 (d, 1H), 7.09-7.13 (d, 2H), 4.16-4.20 (t, 2H), 2.79-2.83 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[S:11][C:10]([C:12]#[N:13])=[CH:9][C:8]=2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[S:11][C:10]([C:12]3[NH:29][N:28]=[N:27][N:13]=3)=[CH:9][C:8]=2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2cc(C#N)sc2Cc2ccc(Cl)cc2)c2ccccc12
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1ccc(-c2cc(-c3nnn[nH]3)sc2Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 110 °C
Yield: 85.8 %

Procedure:
A round-bottomed flask was charged with 5-(4-chlorobenzyl)-4-(4-methylnaphthalen-1-yl)thiophene-2-carbonitrile (170 mg, 0.45 mmol), zinc bromide (338 mg, 1.50 mmol) and sodium azide (97.5 mg, 1.50 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 110° C. and stirred at this temperature until complete. The reaction was cooled to rt and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 161 mg (85%) of product was obtained as a white solid, 1H NMR (CDCl3, 500 MHz) δ 8.05 (d, J=8.46 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J=8.36 Hz, 1H), 7.53 (t, J=7.58 Hz, 1H), 7.42 (t, J=7.53 Hz, 1H), 7.33 (d, J=7.11 Hz, 1H), 7.23 (d, J=7.08 Hz, 1H), 7.14 (d, J=8.25 Hz, 2H), 6.92 (d, J=8.14 Hz, 2H), 3.86 (ABq, 2H, ΔδAB=0.06, JAB=15.90 Hz), 2.70 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 152.61, 145.54, 139.59, 137.96, 135.22, 132.97, 132.76, 132.69, 132.27, 131.09, 130.05, 128.81, 127.55, 126.33, 126.25, 126.20, 126.16, 124.75, 122.29, 34.24, 19.77.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(-c2cc(C)ccn2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc(-c2cc(C)ccn2)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-methylpyridin-2-yl)anisole (1.38 g) in sulfuric acid (3 ml) was added fuming nitric acid (0.5 ml) dropwise at 0° C., and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, 0-5% methanol in dichloromethane) to give 4-(4-methylpyridin-2-yl)-2-nitroanisole (378 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C.O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
To a solution of ethyl 6-[(4,6-diphenyl-2-pyridyl)oxy]hexanoate (3.7 g) in ethanol (100 cc) are added sodium hydroxide pellets (0.6 g). The reaction mixture is refluxed for 1 hour and then concentrated to dryness under reduced pressure. The residue obtained is dissolved in distilled water (150 cc). The pH of the aqueous phase is brought to about 5 by addition of a 2N aqueous solution of hydrochloric acid. It is then extracted with methylene chloride (3×50 cc). The organic phases are combined, washed with distilled water (3×50 cc), dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The solid residue obtained is purified by recrystallization in an n-hexane-ethyl acetate (10-1) mixture (55 cc). (white crystals; m.p.=87°-88° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Br[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([S:9][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Cn1c(S)nc2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(SC(C(=O)O)c2ccccc2)nc2cc(Cl)ccc21
Yield: 775.4 %

Procedure:
5.96 g (0.03M) of 5-Chloro-2-mercapto-1-methylbenzimidazole of C above, 0.5 g (0.03M) of α-bromophenylacetic acid and 6.0 g (0.06M) of triethylamine are dissolved in methylene chloride (200 ml) and the mixture heated to reflux overnight. The basic solution is washed with a diluted HCl solution and a white solid is collected. The crude material is recrystallized from 5 L of acetonitrile to give 6.0 g (60% yield) of the title compound, m.p. 203°-5° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:55]([Si:59]([CH3:70])([CH3:69])[O:60][C:61]1[CH:62]=[C:63]([CH:66]=[CH:67][CH:68]=1)[CH2:64][NH2:65])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:65][CH2:64][C:63]2[CH:66]=[CH:67][CH:68]=[C:61]([O:60][Si:59]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:69])[CH3:70])[CH:62]=2)=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To a solution of 3-Chloro-thiophene-2,5-dicarboxylic acid 2-methyl ester (500 mg, 2.27 mmol) in anhydrous DMF (10 mL) was added triethylamine (1.0 mL, 6.81 mmol), HBTU (1.03 g, 2.72 mmol), HOBT (370 mg, 2.72 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (650 mg, 2.72 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-30% EtOAc in hexane to afford the desired product (0.26 g, 26% yield).
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:15][NH2:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[NH:16][N:15]=[CH:4]2
Reactant: NN
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1cccc2cn[nH]c12
Yield: 93 %

Procedure:
A solution of 2-fluoro-3-trifluoromethylbenzaldehyde (5 g, 26 mmol)), hydrazine hydrate (8.3 mL, 260 mmol) and DMAP (3.17 g, 26 mmol.) in 10 mL pyridine was heated at 100° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried with anhydrous sodium sulfate (Na2SO4). The organic phase was concentrated in vacuo to give 4.5 g of product. The crude product was recrystallized from Et2O/hexane to give the title compound (3.6 g, white solid, mp 90° C.).
Reaction SMILES: Cl.F[C:3]1[C:8]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[CH:18]1.O1CCOCC1>>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:8]2[C:3]([NH:26][C:21]3[C:20]4[CH:19]=[CH:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[N:10]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1cccc2[nH]ccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc3[nH]ccc23)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
2 N HCl (aq) (0.42 mL, 833 μmol) was added to a stirred mixture of 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (171 mg, 833 μmol) and 1H-indol-4-amine (132 mg, 1000 μmol) in 1,4-dioxane (4.00 mL, 46762 μmol) and the brown mixture was heated at 100° C. overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with SiO2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) followed by washing the eluent concentrates with EtOAc to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-1H-indol-4-amine (58 mg, 22%) as a yellow solid. LCMS (API-ES) m/z 318 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ ppm 12.00 (s, 1H) 11.15 (br. s., 1H) 8.77 (dd, J=7.78, 1.76 Hz, 1H) 8.38 (dd, J=4.52, 1.51 Hz, 1H) 8.09 (d, J=6.02 Hz, 1H) 7.53-7.81 (m, 2H) 7.35 (t, J=2.76 Hz, 1H) 6.99-7.19 (m, 2H) 6.90 (dd, J=7.78, 4.77 Hz, 1H) 6.66 (br. s., 1H) 2.55 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH3:15][NH:16][CH2:17][CH2:18][OH:19].C(OCC)(=O)C>C(O)C>[OH:19][CH2:18][CH2:17][N:16]([CH3:15])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: CNCCO
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCO)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a suspension of 2.946 g (13.73 mmol) of 2-chloro-N-(4-nitrophenyl)acetamide in 30 mL of ethanol was added 3.31 mL (41.18 mmol) of 2-(methylamino)ethanol and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature and condensed, then, the residue was treated with ethyl acetate. The organic layer was washed with water and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to give 2.05 g (59%) of the title compound.