Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:15][NH2:16]>N1C=CC=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:15][NH2:16])=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cc1
Solvent: c1ccncc1
Product: NNc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 0 °C

Procedure:
A mixture of 21.1 g. of 2-chloro-5-(4-chlorophenyl)pyridine and 19.5 g. of 95% hydrazine in 200 ml. of pyridine is heated at reflux temperature for 48 hours. The reaction mixture is cooled, poured into an ice-water mixture and filtered. The solid is collected, washed with water and air dried to yield 17.0 g. of the product of the Example as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li]CCCC.B.Cl[C:14]1[C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:32][CH3:33])[N:26]=3)[C:16]=2[N:17]=[C:18]([NH2:20])[N:19]=1>C1COCC1.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>[CH3:33][O:32][CH2:31][C:27]1[N:26]=[C:25]([CH2:24][N:21]2[C:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:14]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)[C:15]=3[N:23]=[N:22]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cscn1
Reactant: COCc1cccc(Cn2nnc3c(Cl)nc(N)nc32)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1cccc(Cn2nnc3c(-c4nc(C)cs4)nc(N)nc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 4-methylthiazole (0.15 mL, 1.65 mmol) in dry THF (7.5 mL) was cooled to −78° C. under nitrogen, treated with n-BuLi (1.0 mL, 1.65 mmol) and stirred for 30 minutes, then ZnCl (1-M, 1.65 mL, 1.65 mmol) was added, and the reaction mixture was warmed to room temperature. 7-Chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (250 mg, 0.825 mmol) was then added followed by Pd(PPh3)4 (48 mg, 0.04 mmol) and the reaction mixture heated to reflux for 1 h. The reaction mixture was cooled to room temperature, quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. The crude product was purified by chromatography (eluant:EtOAc-heptane 1:1 to 2:1) to give the title compound (38 mg, 13%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C(=O)([O-])O.[Na+]>O.C(OCC)C>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][OH:14])=[O:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(NO)c1ccc(CCl)cc1
Yield: 91.6 %

Procedure:
4-Chloromethyl-benzoyl chloride (18.9 g) (0.1 mol) and 13.8 g (0.2 mol) of hydroxylamine hydrochloride are suspended in 200 ml of water and 150 ml of diethyl ether. 25.2 g (0.3 mol) of sodium hydrogen carbonate are added while stirring. After 30 minutes the product is filtered off under suction and washed with water and diethyl ether. After drying in a high vacuum at room temperature there are obtained 17 g of white α-chloro-N-hydroxy-p-toluamide of m.p. 120°-145° C. (dec.).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CS(O)(=O)=O>C1(C)C=CC=CC=1.CCOCC>[C:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1
Reactant: CCCCCCCCCCO
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOC(=O)c1ccc[n+]([O-])c1
Reaction time: 19 h
Yield: 75 %

Procedure:
Nicotinic acid N-oxide (5.00 g, 36 mmol), decyl alcohol (5.86 g, 37 mmol) and methanesulfonic acid (3.70 g, 38.5 mmol) were stirred and heated to reflux in toluene (50 mL), in a flask equipped with a condenser and a Dean-Stark trap for 19 hours. The reaction mixture was then cooled, diluted with ether and washed successively with water, aqueous sodium bicarbonate and brine. The toluene/ether solution was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from ligroine (100 mL) to give 7.50 g (27 mmol) of decyl nicotinate N-oxide, mp 80.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[NH3:18]>CC(O)C>[Cl:1][C:2]1[N:6]([C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH2:18])[CH:12]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Clc1cc(-n2c(Cl)nc3ccccc32)ncn1
Reactant: N
Solvent: CC(C)O
Product: Nc1cc(-n2c(Cl)nc3ccccc32)ncn1
Temperature: 50 °C

Procedure:
A mixture of 2-Chloro-1-(6-chloro-pyrimidin-4-yl)-1H-benzoimidazole (500 mg, 1.89 mmol) and 10 mL 2 M Ammonia in 2-propanol is heated at 50° C. in a sealed tube for overnight. The reaction mixture is then cooled to room temperature, concentrated and treated with 10 mL H2O. The solid is collected by filtration and washed with water, dried to afford the title compound as a solid: 1H NMR 400 MHz (DMSO-d6) δ 8.50 (s, 1H), 7.72-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.44 (s, 2H), 7.37-7.31 (m, 2H), 6.71 (dd, J=1.2 Hz, 1H); MS m/z 246.1 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:20][CH:19]=4)[CH:16]=[C:11]3[C:10]([CH3:32])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:32][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Nc4ccc(CN5CCN(C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ncc(Nc3ccc(CN4CCN(C)CC4)cc3)cc12
Temperature: 60 °C

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (166) (40 mg, 0.657 mmol) in CHCl3 (10 mL) was added trifluoroacetic acid (6 mL) and the reaction mass heated at 60° C. overnight. After completion of the reaction the solvents were completely distilled off and diluted with water and the pH was adjusted to 9 and extracted with chloroform twice. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed and the crude material was passed through 100-200 mesh silica gel, eluting with 8% MeOH/CH2Cl2 obtained pure 3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-amine 167 as a pale yellow colored solid (10 mg). 1H NMR (400 MHz, CDCl3) δ: 8.38 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 7.21 (d, 1H), 7.19 (d, J=8.41, 1H), 7.19 (s, 1H), 6.89 (d, J=7.92, 1H), 3.46 (s, 2H), 2.54 (m, 8H), 2.31 (s, 3H), 2.05 (s, 3H); MS m/z 336.9 (M+H)+.
Reaction SMILES: [H-].[Na+].O=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[Cl:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[CH2:28]P(=O)(OCC)OCC.Cl>CN(C=O)C.C(Cl)Cl.CC(C)=O>[Cl:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[CH:28]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: CCOP(=O)(Cc1ccccc1Cl)OCC
Reactant: CC1C(=O)CC[C@@]2(C)[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1C(=O)CC[C@@]2(C)[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=Cc3ccccc3Cl)CC[C@@H]12
Temperature: 70 °C
Reaction time: 1.83 h

Procedure:
Sodium hydride (60%, 26 mg, 0.66 mmole) was added to a solution of 101 mg. (0.33 mol) of 17-keto-4-methyl-5α-androstan-3-one (F) and 173 mg (0.66 mol) of diethyl 2-chlorobenzylphosphonate in 1.0 ml of dry DMF at room temperature. The mixture was heated at 70° C. in a nitrogen atmosphere with stirring for 110 minutes, cooled, poured into 0.5N HCl (20 ml) and extracted with methylene chloride (3×). The organic phases were combined, washed with water (3×), saturated NaCl solution and dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to yield a tan, gummy solid. Flash chromatography of the crude solid was conducted on a silica gel 60×20 mm column, and eluted with 4:1 methylene chloride/acetone in 6 ml. fractions. Fractions 18-24 contained the product which were combined and evaporated to yield a white solid, mp 205°-208° C., yielding one spot on silica gel TLC using 4:1 methylene chloride/acetone. The proton NMR confirmed the assigned structure for 39.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
To a solution of Example 66 (0.100 g, 0.202 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 1.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.035 g, 36% yield). MP: 260-262° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.16 (s, 1H), 8.22 (s, 1H), 8.06 (dd, J=7.9, 1.5 Hz, 1H), 7.78 (m, 1H), 7.50 (dt, J=8.0, 1.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.37-7.31 (m, 5H), 6.86 (t, J=1.5 Hz, 1H), 6.82 (dt, J=7.6, 2.3 Hz, 1H), 6.65 (td, J=10.9, 2.3 Hz, 1H), 5.50 (s, 2H). Mass: 480.02 (M++1).
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:24]1([CH2:36][C:37]([NH2:39])=[O:38])[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1>>[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]2[C:4]1[C:3](=[O:23])[NH:39][C:37](=[O:38])[C:36]=1[C:24]1[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2c(OCc3ccccc3)cccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2c(OCc3ccccc3)cccc12

Procedure:
Beginning with 7-(benzyloxy)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Product: Cc1c(NS(=O)(=O)C(C)C)cccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product from Example 2B and isopropylsulfonylchloride were processed as described in Example 3 to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ1.23 (d, 6H, J=6.5 Hz), 2.39 (s, 3H), 3.18 (m, 1H), 4.04 (s, 4H), 6.91 (dd, 1H, J=7.5, 1.6 Hz), 6.97 (m, 2H), 7.19 (m, 2H), 7.26 (m, 8H), 8.86 (s, 1H); MS (APCI+) m/z 409 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(O)C>[Cl:1][C:2]1[C:3]2[C:10]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)n1cc(I)c2c(Cl)ncnc21
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cn(C(C)C)c3ncnc(Cl)c23)cc1
Temperature: 105 °C

Procedure:
A mixture of 4-chloro-5-iodo-7-isopropylpyrrolo[2,3-d]pyrimidine (2.8 g), 4-methoxybenzeneboronic acid (1.32 g), bis(triphenylphosphine)palladium (II) chloride (625 mg), toluene (85 ml), ethanol (11 ml), water (22 ml) and sodium bicarbonate (2.2 g) was heated under nitrogen at 105° C. for 18 hours. The mixture was allowed to cool to ambient temperature and then partitioned between ethyl acetate (100 ml) and brine (100 ml). The organic layer was separated and the aqueous layer was washed with ethyl acetate (2×50 ml). The combined organic layers were washed with water, dried, filtered and evaporated under reduced pressure to give a black oil which solidified on cooling. This material was purified by flash column chromatography on silica using cyclohexane/ethyl acetate (7:3) as the mobile phase. Appropriate fractions were combined and concentrated under reduced pressure to give a yellow oil which solidified on standing to give 4-chloro-7-isopropyl-5-(4-methoxyphenyl)pyrrolo[2,3-d]pyrimidine. The structure was confirmed by 1H nmr.
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH:43][C:44]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[C:12]([Cl:11])[CH:13]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 70%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:28])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:28][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Agent: Cl
Product: O=C(Cc1ccncc1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1

Procedure:
4-Pyridylacetic acid hydrochloride and the product from Example 99A were processed using method analogous to that described in Example 98 to afford the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.86 (dd, J=7.1, 1.6 Hz, 1H), 8.56 (dd, J=4.1, 1.8 Hz, 1H), 8.45-8.53 (m, 2H), 7.57-7.66 (m, 2H), 7.37-7.48 (m, 2H), 7.26-7.35 (m, 2H), 7.07 (dd, J=7.0, 4.1 Hz, 1H), 3.82 (s, 2H); MS (ESI) m/z 364 (M+H)+; Anal. calculated for C19H14ClN5O.0.25H2O: C, 61.69; H, 3.97; N, 18.68. Found C, 61.59; H, 3.61; N, 18.68.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1)=O.[C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:11]>C(Cl)(Cl)Cl>[CH3:9][S:8][C:5]1[S:4][C:3]([CH:1]=[CH:12][C:10]#[N:11])=[CH:7][CH:6]=1
Reactant: CSc1ccc(C=O)s1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C=CC#N)s1
Yield: 79.2 %

Procedure:
A solution of 2-formyl-5-methylthiothiphene (9.11 g., 58 mmole) and cyanomethylenetriphenylphosphorane (19.1 g., 64 mmole) in chloroform (200 ml.) was stirred at room temperature for 1 hr., and was then heated under reflux for 10 mins. to complete the reaction. The solvent was removed, and the residue was triturated with dry ether (50 ml.). Colourless crystals of triphenylphosphine oxide (m.p. 156°-157°), were filtered off, and were washed with ether (10 ml.). The combined filtrates were evaporated, and the dark red oily residue was distilled under reduced pressure to give 3-(5-methylthiothien-2-yl)-acrylonitrile (8.33 g., 80%) as a pale-yellow oil, b.p. 124°-135°/0.7 mm., λmax. 350, 241 nm, (ε 3440, 1460) [Found (on a redistilled sample): C, 52.9; H, 3.8; N, 7.4; S, 35.7. C8H7NS2 (181.3) requires C, 53.0; H, 3.9; N, 7.7; S, 35.4%].
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([CH:25]=O)=[CH:15][CH:14]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:27][CH2:28][CH2:29][CH2:30][P:31](=[O:34])([OH:33])[OH:32].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([CH2:25][NH:27][CH2:28][CH2:29][CH2:30][P:31](=[O:32])([OH:34])[OH:33])=[CH:15][CH:14]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ccc(C=O)cc2-c2ccccc2)nc1
Reactant: NCCCP(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCc1ccc(-c2ccc(CNCCCP(=O)(O)O)cc2-c2ccccc2)nc1
Temperature: 50 °C
Yield: 33.1 %

Procedure:
To a solution of 6-(5-hexylpyridin-2-yl)biphenyl-3-carbaldehyde (80 mg, 0.233 mmol) and (3-aminopropyl)phosphonic acid (32.4 mg) in methanol was added tetrabutylammonium hydroxide (1M in MeOH, 0.23 mL). The reaction mixture was heated to 50° C. for 30 min with stirring, then sodium cyanoborohydride (41 mg, 0.65 mmol) was added. The reaction mixture was heated to 50° C. with stirring for 3 h. After cooling to RT, the mixture was concentrated and purified by MPLC (0-100% ethyl acetate in hexanes) to give 36 mg of the desired product as a colorless solid. 1H NMR (300 MHz, CD3OD) δ 8.34 (d, J=1.76 Hz, 1H), 7.58-7.63 (m, 3H), 7.41 (dd, J=2.34, 8.20 Hz, 1H), 7.20-7.25 (m, 3H), 7.11-7.16 (m, 2H), 6.91 (d, J=7.91 Hz, 1H), 4.21 (s, 2H), 3.11 (t, J=6.30 Hz, 2H), 2.61 (t, J=7.62 Hz, 2H), 1.92-2.07 (m, 2H), 1.55-1.74 (m, 4H), 1.31 (br. s., 6H), 0.86-0.92 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][O:14][C:15](=[O:34])[C:16]1[C:17](=[CH:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])=[CH:24][CH:25]=1)[C:18]([O:20][CH3:21])=[O:19]>CC(C)=O>[CH3:13][O:14][C:15](=[O:34])[C:16]1[C:17](=[CH:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:24][CH:25]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(Oc2ccccc2N)cc1C(=O)OC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Oc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 126.4 %

Procedure:
A solution of 3-nitrobenzoyl chloride (0.43 g, 2.3 mmol) in dry acetone (2ml) was added slowly to a solution of 4-(2-aminophenoxy)phthalic acid dimethyl ester (0.63 g, 2.09 mmol) and TEA (0.35 ml, 2.5 mmol) in dry acetone (2ml) at 0° C. The mixture was stirred at room temperature for 20 hours, filtered and the filtrate evaporated to dryness in vacuo. The crude product was purified on silica gel (eluent: methylene chloride/ethyl acetate (95:5)) to give 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester (yield: 1.19 g (47%)) as a golden oil. 1H—NMR (CDCl3) in ppm: δ 3.9 (6H,2xs); 7.02 (1H,d.d.); 7.1-7.25 (2H,m); 7.25-7.35 (2H,m); 7.7 (1H,t); 7.83 (1H,d); 8.1 (1H,d.t.); 8.3 (1H, broad s); 8.4 (1H,m); 8.54 (1H,d.d.); 8.65 (1H,m).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:7]=1)=O.[OH-].[Na+]>>[CH3:17][N:13]([CH2:12][C:8]1[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCN(C)Cc1cccc(NC(=O)C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Product: CCCN(C)Cc1cccc(N)n1

Procedure:
This material was prepared in analogy to example 86 step B] from 2,2-dimethyl-N-{6-[(methyl-propyl-amino)-methyl]-pyridin-2-yl}-propionamide (0.755 g) and 3M aqueous NaOH (5.73 mL) as a brown liquid (0.53 g). MS (ESI): 180.2 (MH+).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:27]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]3[N:27]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=5)[N:11]4[N:10]=3)=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(F)nc4)nn23)c1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5cccc(S(C)(=O)=O)c5)n4n3)cn2)CC1
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A solution of N-(6-fluoropyridin-3-yl)-5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (250 mg, 0.65 mmol) in 1-methylpiperazine (500 mg, 5 mmol) was heated at 140° C. After 16 h, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting solution was washed with water, and the collected organic was concentrated. Purification by preparative thin layer chromatography afforded the desired product (101 mg). LCMS (ESI) m/z: 464.2. 1H NMR (400 MHz, CDCl3), δ: 8.69 (s, 1H), 8.30 (s, 1H), 8.16-8.14 (d, J=8 Hz, 1H), 8.03-8.01 (d, J=8 Hz, 1H), 7.81-7.67 (m, 2H), 7.50-7.45 (m, 2H), 6.97 (s, 1H), 6.68-6.64 (m 2H), 3.42-3.34 (m, 4H), 3.10 (s, 3H), 2.48-2.45 (m, 4H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2([OH:19])[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][CH:10]=1>CCOC(C)=O.CO>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][CH2:12][C:13]1([OH:19])[CH2:14][CH2:15][S:16][CH2:17][CH2:18]1
Reactant: NCCOc1cccc(C#CC2(O)CCSCC2)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCOc1cccc(CCC2(O)CCSCC2)c1

Procedure:
Hydrogenation of 4-((3-(2-aminoethoxy)phenyl)ethynyl)tetrahydro-2H-thiopyran-4-ol was conducted following the method used to prepare Example 2 except that EtOAc-MeOH (90%) was used as the reaction solvent. Example 11 was isolated as a colorless oil. Yield (0.179 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ 7.13 (t, J=8 Hz, 1H), 6.34-6.88 (m, 3H), 4.26 (br s, 1H), 3.86 (t, J=6.0 Hz, 2H), 2.57-2.88 (m, 4H), 2.53-2.56 (m, 2H), 2.32-2.37 (m, 2H), 1.73-1.78 (m, 2H), 1.42-1.62 (m, 6H).