Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:20][CH3:21])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>N1C=CC=CC=1>[NH3:1].[CH2:22]([S:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:20][CH3:21])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:26])=[O:25])[CH3:23]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCCCN1CCC(CC)(c2cccc(N)c2)CC1
Solvent: c1ccncc1
Product: CCCCCCN1CCC(CC)(c2cccc(NS(=O)(=O)CC)c2)CC1
Product: N
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.4 %

Procedure:
To 4-(3-aminophenyl)-4-ethyl-N-hexylpiperidine (Preparation 64, 50.0 mg, 0.174 mmol) in anhydrous pyridine (4 ml) under nitrogen at 0° C. was added ethanesulfonyl chloride (0.2 ml, 1.15 mmol). The solution was stirred at room temperature for 48 h. Ice (5 g) was added and, after 30 min, the reaction mixture was extracted with dichloromethane (10 ml). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by silica (5 g) column chromatography, eluting with ethyl acetate:hexane:0.880 ammonia (50:50:1) and then methanol:ethyl acetate:0.880 ammonia (10:89:1) to give the title compound as an oil (22 mg, 30%).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=[O:25])[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH3:26][C:27](C)([O-])[CH3:28].[K+].CN1C[CH2:36][CH2:35][C:34]1=[O:38].BrCCC>C(O)CC>[CH:7]1[C:8]2=[C:19]3[C:18]([C:17]4[C:20]5[C:13](=[CH:12][CH:11]=[CH:10][C:9]2=5)[CH:14]=[CH:15][CH:16]=4)=[CH:1][CH:2]=[C:3]([C:24]([O:38][CH2:34][CH2:35][CH3:36])=[O:25])[C:4]3=[C:5]([C:21]([O:23][CH2:26][CH2:27][CH3:28])=[O:22])[CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: CN1CCCC1=O
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: [K+]
Solvent: CCCO
Solvent: CCCBr
Product: CCCOC(=O)c1ccc2c3cccc4cccc(c5ccc(C(=O)OCCC)c1c25)c43
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.18 g (0.56 mmol) of perylene-3,4-dicarboxylic anhydride is suspended in 10 ml of dried n-propanol, 0.15 g (1.43 mmol) of potassium t-butoxide is added, and the suspension is stirred at room temperature for 0.5 hour with the exclusion of moisture. During the course of the reaction, a colour change from brown to yellow can be observed, during which the precipitate dissolves. The solvent is then distilled off, and first 10 ml of N-methylpyrrolidone and then 0.20 ml (2.4 mmol) of 1-bromopropane are added, and the yellow solution is stirred at room temperature for 17 hours. The solvent is distilled off in vacuo, the yellow residue is chromatographed on silica gel using chloroform. Yield 0.16 g (68%), m.p. 253° C., Rf (CHCl3 /silica gel)=0.48. UV (CHCl3): λmax (ε)=460 nm (27944), 437 (23875), 340 (1900), 327 (2050), 260 (32991). Fluorescence (CHCl3):λmax (Irel)=482 nm (1), 509 (0.69), solid fluorescence: λmax =595 nm.
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.BrC1CC1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1C#N>C(O)(=O)C.O>[CH:5]1([C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[O:2])[CH2:3][CH2:4]1
Reactant: C1CCOC1
Reactant: N#Cc1ccccc1F
Agent: BrC1CC1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1F)C1CC1
Yield: 29.4 %

Procedure:
To a stirred mixture of 10 parts of magnesium and 72 parts of tetrahydrofuran there were added portionwise 50 parts of bromocyclopropane, keeping the temperature below 10° C. At reflux temperature, there was added a solution of 50 parts of 2-fluorobenzenecarbonitrile in 72 parts of tetrahydrofuran. Stirring at reflux temperature was continued until completion of the reaction. The reaction mixture was cooled on ice (0°-5° C.) and decomposed with a mixture of ice, water and acetic acid. The product was extracted with trichloromethane (3×) and the combined extracts were washed with water (2×), dried, filtered and evaporated. The residue was distilled (1.33 Pa; 78°-105° C.) (2×), yielding 19.8 parts (29.4%) of cyclopropyl (2-fluorophenyl)methanone; bp. 100°-103° C. (at 1.3 Pa) (interm. 17).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10](=[CH2:13])[C:11]#[N:12].[OH-].[Na+]>O>[C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:13]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(Cl)C#N
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccnn1-c1ccccc1
Reaction time: 6 h

Procedure:
To a mixture consisting of 680 parts water, 216 parts of phenylhydrazine and 164 parts of 2-chloroacrylonitrile 220 parts of a 30% sodium hydroxide solution are added dropwise at room temperature. After six hours the reaction is completed. The resulting 1-phenyl-5-aminopyrazole is isolated from that phase which has been separated by the addition of sodium chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C@@H:9]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2].[CH2:34](I)[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C@@H:9]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:34][CH3:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(C)c1
Reactant: CCI
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCC[C@@H](SCc2c(C)cc(C)cc2C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of [(1R, 2R, 3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-carbamic acid tert-butyl ester+(1S, 2S, 3S)diastereomer (3.0 g, 6.08 mmol) was treated with ethyl iodide according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=3/1) [(1R, 2R, 3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-ethyl-carbamic acid tert-butyl ester+(1S, 2S, 3S)diastereomer (1.20 g, 38%) was obtained.
Reaction SMILES: CO[CH:3]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=1[C:9]([OH:11])=O)=O.C([NH2:27])=O.[CH2:28]([OH:30])C>CC(C)=O>[CH3:28][O:30][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH2:3][C:4]1[NH:27][C:9](=[O:11])[C:8]2[C:7](=[CH:15][CH:14]=[C:13]([CH3:16])[CH:12]=2)[N:6]=1
Reactant: NC=O
Reactant: COc1cccc(C(OC)C(=O)Nc2ccc(C)cc2C(=O)O)c1
Reactant: CCO
Solvent: CC(C)=O
Product: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)[nH]2)c1
Temperature: 160 °C
Yield: 49 %

Procedure:
A mixture of 3.15 g (9.6 mmol) of 2-(2,5-dimethoxyphenylacetylamino)5-methylbenzoic acid (m.p. 163° to 164.5° C.) obtainble by the same method as in Synthesis example 2 and 0.90 g (20ml) of formamide were heated at 160° C. for 3 hours. After cooling, the solidified residue was added to a mixed solution of ethanol (100 ml) and acetone (100 ml) and dissolved therein by heating. After cooling, the precipitated crystals were collected by filtration to obtain 1.45 g (yield 49 %) of 2-(2,5-dimethoxyphenylmethyl)-6-methyl-4(3H)-quinazolinone.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]=[O:10].C[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:6]([CH3:7])=[C:5]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)[S:4][C:3]=2[CH:9]=[O:10])=[CH:15][CH:14]=1
Reactant: Cc1c(I)sc(C=O)c1Br
Reactant: COc1ccc(B(O)O)cc1
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)cc1
Yield: 109.6 %

Procedure:
Starting from 3-bromo-5-iodo-4-methylthiophene-2-carbaldehyde (3.2 g, 9.7 mmol, Compound III) and 4-methoxyphenylboronic acid (3.2 g, 21 mmol, 2.2 eq), the title compound (3.3 g, 94%, m.p. 223-25° C.) was synthesized in essentially the same manner as described in Example 1, Steps 1 and 4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][Cl:23])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)CCCCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)CCCCCl)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a stirred mixture of 3.6 g (16 mmol) of 3,5 -di-tert-butyl-4-hydroxyaniline and 1.3 g (16 mmol) of pyridine in 50 ml of ether cooled to 0° C. there was slowly added 2.5 g (16 mmol) of 5-chlorovalerylchloride. The reaction mixture was allowed to warm to 25° C. and stirred for 15 hours following which the mixture was diluted with 100 ml of ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to 5.8 g of solid. The solid was triturated in hexane and filtered to yield 5.5 g (16 mmol) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-chlorovaleramide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH3:15][SiH:16]([CH3:29])[O:17][Si:18]([CH3:28])([CH3:27])[O:19][Si:20]([CH3:26])([CH3:25])[O:21][SiH:22]([CH3:24])[CH3:23].[C:30]1(C)[C:31](C)=[CH:32][CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH2:4][Si:22]([CH3:23])([CH3:24])[O:21][Si:20]([CH3:25])([CH3:26])[O:19][Si:18]([CH3:27])([CH3:28])[O:17][Si:16]([CH2:4][CH2:3][CH2:2][CH2:1][O:5][C:34]2[CH:33]=[CH:32][C:31]([N+:12]([O-:14])=[O:13])=[CH:30][CH:35]=2)([CH3:29])[CH3:15])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: C=CCCOc1ccc([N+](=O)[O-])cc1
Reactant: C[SiH](C)O[Si](C)(C)O[Si](C)(C)O[SiH](C)C
Reactant: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Yield: 75 %

Procedure:
To a solution of the above 4-(3-butenyloxy)nitrobenzene (1) (4.27 g; 22.1 mmol), 1,1,3,3,5,5,7,7-octamethyltetrasiloxane (2.97 g; 9.98 mmol) dissolved in 20 mL of toluene and Karsted catalyst (0.25 mL; a 2% xylene solution of platinum divinyl tetramethyldisiloxane complex) were added. The reaction solution was heated to reflux for 21 hours in a nitrogen atmosphere, and then subjected to a reduced pressure to remove toluene. The obtained materials were purified by column chromatography to obtain a light yellow oily material of 1,7-bis(4-nitrophenoxybutyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (2b) (5 g, 75% of yield) represented by the following formula.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2.[NH3:17].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl.O=[Mn]=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:17])=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]21[O:16][CH2:15][CH2:14][O:13]2
Reactant: N
Reactant: O=Cc1ccc2c(c1)CCC1(C2)OCCO1
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Following the literature procedure of Lai, G. et al. (Synleft, 2001, 230-231), a stirred solution of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbaldehyde (440 mg, 2.0 mmol) in THF (2 mL) was charged with NH3 (2M solution in isopropanol, 15 mL, 30 mmol, 15 eq) and anhydrous MgSO4 (3.64 g, 30 mmol, 15 eq). After 1 hour, MnO2 (Aldrich, 85%, 3.1 g, 30 mmol, 15 eq) was added in small portions and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with CH2Cl2 (40 mL) and filtered through Celite. The filtrate was concentrated in vacuo to give 0.42 g (100%) of 3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-6′-carbonitrile as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 1H), 7.40 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 4.03 (s, 4H), 3.02 (s, 2H), 3.00 (t, 2H, J=6.9 Hz), 1.96 (t, 2H, J=6.9 Hz). The material was sufficiently pure and it was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][C:4](=[O:14])[CH:3]=1.CS(C1C=CNC(=O)C=1)(=O)=O.[CH2:26]([C:29]1[CH:30]=[N:31][C:32]([N:35]2[CH2:40][CH2:39][CH:38](CS([O-])(=O)=O)[CH2:37][CH2:36]2)=[N:33][CH:34]=1)[CH2:27][CH3:28].CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>>[C:8]1([C:7]2[C:2]([O:1][CH:38]3[CH2:39][CH2:40][N:35]([C:32]4[N:31]=[CH:30][C:29]([CH2:26][CH2:27][CH3:28])=[CH:34][N:33]=4)[CH2:36][CH2:37]3)=[CH:3][C:4](=[O:14])[NH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1cc(O)c(-c2ccccc2)c[nH]1
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CS(=O)(=O)c1cc[nH]c(=O)c1
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3-c3ccccc3)CC2)nc1

Procedure:
The compound in Step C was prepared according to the procedures described in Example 1 substituting 4-hydroxy-5-phenylpyridin-2(1H)-one for 4-hydroxy-1-(4-(methylsulfonyl)pyridine-2(1H)-one and 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate for tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate in Step D. MS (ESI) 391 (M+H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[OH:32])([O-:24])=[O:23].O.C(OCC)(=O)C>CN(C)C=O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)=[O:32])([O-:24])=[O:23]
Reactant: COc1ccc(C(O)c2ccccc2[N+](=O)[O-])cn1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccccc2[N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Pyridinium dichromate (18.7 g) was added to a stirred, cooled (0° C.) solution of (2-nitrophenyl)-(6-methoxypyridin-3-yl)methanol (2.0 g) in dimethylformamide (60 ml). After 2 hours at 0° C. water (100 ml) and ethyl acetate (50 ml) were added and the mixture allowed to warm to room temperature. The organic layer was separated and the aqueous extracted with ethyl acetate (3×100 ml). The combined organics were washed with water (2×100 ml) then brine (100 ml), dried (magnesium sulphate) then evaporated to dryness to give the title compound as a solid (1.90 g). mp 94°-95° C. Rf =0.35 in 33% ethyl acetate/petroleum ether (60-80) on silica plates; 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 6.63 (1H, d, J=9 Hz), 7.47 (1H, dd, J=1 and 8 Hz), 7.70 (1H, dd, J=8 Hz), 7.78 (1H, dd, J=8 Hz), 8.12 (1H, dd, J=3 and 9 Hz), 8.25 (1H, dd, J=1 and 8 Hz), 8.36 (1H, d, J=3 Hz); MS, m/z 258 for M+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:26]4[CH:27]=[CH:22][CH:23]=[C:24]([CH:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:25]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
4-(3-Bromo-phenyl)-1-methyl-piperidine hydrochloride was prepared from 4-(3-bromo-phenyl)-piperidine; hydrochloride (1.0 g, 3.6 mmol) in a manner analogous to Step 34c. The reaction product was isolated as a white solid (0.43 g, 41%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.52 (s, 1H), 7.47-7.41 (m, 2H), 7.37-7.21 (m, 2H), 3.52-3.41 (m, 2H), 3.10-2.95 (m, 2H), 2.85-2.78 (m, 1H), 2.75 (s, 3H), 2.15-2.78 (m, 4H). 61b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(1-methyl-piperidin-4-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (90.0 mg, 0.310 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.031 g, 26%). MP=208-210° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 8.10 (d, J=7.3 Hz, 2H), 7.66 (d, J=6.6 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.31-7.25 (m, 1H), 7.02 (t, J=7.4 Hz, 1H), 6.91-6.85 (m, 2H), 3.10 (s, 3H), 3.01 (d, J=10.9 Hz, 2H), 2.57-2.45 (m, 1H), 2.35 (S, 3H), 2.11-2.03 (m, 2H), 1.92-1.83 (m, 4H). MS=462 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O.C(O)(C(F)(F)F)=O.CCOC(C)=O>[C:16]1([NH:15][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Oc1ccc(-c2ccc(Nc3ccccc3)nn2)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-chloro-pyridazin-3-yl)-phenol (Step 2, 1 g, 4.84 mmol) and aniline (1.35 g, 14.52 mmol) in 20 mL of DMSO was added 5 drops of TFA. The reaction was heated to 80° C. for 16 h. The solution was cooled to RT and diluted with 100 mL of EtOAc. The organic phase was washed with 40 mL of water, 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% EtOAc/hexane to EtOAc) to give the title compound as a white solid. MS (ESI pos. ion) m/z: 264.2(M+H). Calc'd Exact Mass for C16H13N3O: 263.29.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1.C(=O)(OC(C)(C)C)[NH2:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[NH2:16][CH2:9][C:8]1[CH:11]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=[CH:6][C:7]=1[OH:12]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(trifluoromethoxy)salicylaldehyde (4.85 mmol, 1.0 g), tert-butyl carbamate (14.55 mmol, 1.70 g), triethylsilane (14.55 mmol, 2.3 mL), trifluoroacetic acid (9.7 mmol, 0.72 mL) in acetonitrile was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and purified by silica gel chromatography (15%-100% EtOAc/hexane). The resulting yellow solid was then dissolved in a mixture of TFA (10 mL) and dichloromethane (20 mL) and stirred for 2 hours at room temperature. The volatile solvents were then removed by rotovap to afford 2-(aminomethyl)-4-(trifluoromethoxy)phenol as a yellow oil. 1H NMR (CD3OD) 7.28 (s, 1H), 7.22 (m, 1H), 6.97 (m, 1H), 4.13 (s, 2H), 1.59 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: N#Cc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (72 mg, 85%), MS (ISP) m/z=338.4 [(M+H)+], mp 224.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(#N)C.O>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH2:13][O:14][CH3:15])[N:10]=2)[N:5]=[CH:6][CH:7]=1.[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][O:14][CH3:15])[C:3]=12
Reactant: Ic1ccnc2c[nH]nc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COCCn1cc2nccc(I)c2n1
Product: COCCn1ncc2nccc(I)c21
Temperature: 120 °C
Yield: 24.25 %
Yield: 24.25 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (100 mg, 0.408 mmol), 1-bromo-2-methoxyethane (56.7 mg, 0.408 mmol) and cesium carbonate (266 mg, 0.816 mmol) were combined in DMF (5 mL). The mixture was heated at 120° C. for 1 hour, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-70% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to give 7-iodo-2-(2-methoxyethyl)-2H-pyrazolo[4,3-b]pyridine (30 mg, 24.25% yield) and 7-iodo-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridine (30 mg, 24.25% yield). MS [M+H] found 304.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[B:11]([OH:13])[OH:12])[C:5]([OH:7])=[O:6].[CH3:14]N(C)C=O.C(OCC)C.C[Si](N=[N+]=[N-])(C)C.CCCCCC>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:14])=[O:6])[CH:8]=[CH:9][C:10]=1[B:11]([OH:13])[OH:12]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)c1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a mixture of 3-chloro-4-(dihydroxyboryl)benzoic acid (1.00 g, 5.10 mmol), N,N-dimethylformamide (10 mL) and diethyl ether (1 ml) was added dropwise a 0.6 M trimethylsilylazide-hexane solution (10.2 mL, 6.12 mmol), and the resulting mixture was stirred overnight at room temperature. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration and recrystallized from water to give the title compound (0.46 g, yield 42%) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C@@:16]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:51])([F:50])[F:49])=[N:26][N:27](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1.C([SiH](CC)CC)C>ClCCl>[CH3:8][N:9]1[C:17]2[C@@:16]3([CH3:21])[C:18]([CH3:19])([CH3:20])[C@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:49])([F:50])[F:51])=[N:26][NH:27][CH:28]=1
Reactant: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c(=O)n1Cc1c[nH]nc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.3 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of (4S,7R)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (210 mg, 0.35 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 3.5 h. Triethylsilane (56 μL, 0.35 mmol) was added and the solution was stirred for 5 min, and then evaporated and held under high vacuum overnight. The residue was taken up in dichloromethane and water and the pH was adjusted to ˜7 by adding saturated sodium bicarbonate solution. The layers were separated and the organic layer was dried (magnesium sulfate), filtered, evaporated, and chromatographed, eluting with 1-3% methanol/ethyl acetate to give (4S,7R)-1,7,8,8-Tetramethyl-2-(3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (86 mg, 69%). ES(+)-MS (M+H) 355.